Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males.However,the mechanisms by which testosterone acts on lipid metabolism are not yet fully unders...Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males.However,the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood,especially in teleosts.In this study,cyp17a1-/-zebrafish(Danio rerio)exhibited excessive visceral adipose tissue(VAT),lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis(DNL)enzymes.The assay for transposase accessible chromatinwithsequencing(ATAC-seq)results demonstrated that chromatin accessibility of DNL genes was increased in cyp17a1-/-fish compared to cyp17a1+/+male fish,including stearoyl-CoA desaturase(scd)and fatty acid synthase(fasn).Androgen response element(ARE)motifs in the androgen signaling pathway were significantly enriched in cyp17a1+/+male fish but not in cyp17a1-/-fish.Both androgen receptor(ar)-/-and wildtype(WT)zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue,lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis enzymes.The Ar agonist BMS-564929 reduced the content of VAT and lipid content,and down-regulated acetyl-CoA carboxylase a(acaca),fasn,and scd expression.Mechanistically,the rescue effect of testosterone on cyp17a1-/-fish in terms of phenotypes was abolished when ar was additionally depleted.Collectively,these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish,thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.展开更多
Although significant advances have been made in understanding the pathophysiology of psychiatric disorders(PDs),therapeutic advances have not been very convincing.While psychotropic medications can reduce classical sy...Although significant advances have been made in understanding the pathophysiology of psychiatric disorders(PDs),therapeutic advances have not been very convincing.While psychotropic medications can reduce classical symptoms in patients with PDs,their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes,obesity and non-alcoholic fatty liver disease(NAFLD).The mechanism(s)underlying these metabolic abnormalities is not clear;however,lipid/fatty acid accumulation due to enhanced de novo lipogenesis(DNL)has been shown to reduce membrane fluidity,increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities.Intriguingly,emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity,diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs.In support of this,several adjunctive drugs comprising of anti-oxidants and antiinflammatory agents,that are used in treating PDs in combination with psychotropic medications,have been shown to reduce insulin resistance and development of NAFLD.In conclusion,the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities,and a new avenue for translational research and therapeutic drug designing in PDs.展开更多
Hatchery-roared juvenile black sea breams are characterized by a low level of highly unsaturated fatty acids in their bodies, as compared with wild fish. To assess the effect of docosahaxaenoic acid （DHA） on lipegen...Hatchery-roared juvenile black sea breams are characterized by a low level of highly unsaturated fatty acids in their bodies, as compared with wild fish. To assess the effect of docosahaxaenoic acid （DHA） on lipegenic and lipelysis enzymes, one-year fish were roared on a casein-based purified diet and a DHA fortified diet （ 1.5% DHA ethyl ester/kg diet） for 60 d, followed with a period of 55 d for starvation. Dietary DHA was effectively incorporated into the fish body. Fortification of DHA depressed activities of glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase as lipogenic enzymes in the hepatopancroas and intraperitoneal fat body. Carnitine palmitoyltransferase as lipolysis enzyme in the hepatopancreas was active in the DHA fortified fish. Starvation after feeding experiment induced increased carnitine palmitoyltransferase activity in both control and DHA fortified fish and the activity remained higher in the DHA fortified fish, while the monoenes were selectively consumed prior to highly unsaturated fatty acids. These results indicated that dietary DHA depressed lipogenesis and activated lipolysis.展开更多
This experiment studied hepatic lipogenesis associated with biochemical changes in overfed Landaise Geese and China Xupu geese. Twenty healthy male Landaise geese and 20 healthy male Xupu geese, hatched on the same da...This experiment studied hepatic lipogenesis associated with biochemical changes in overfed Landaise Geese and China Xupu geese. Twenty healthy male Landaise geese and 20 healthy male Xupu geese, hatched on the same day under the same feeding conditions, were selected as experimental animals. The animals were divided into two groups and each breed served as an experimental group. Per goose of per experimental group served for a repeat. Brown rice was selected as test diet. After overfeeding for 21 d and then slaughtering, the biochemical changes of hepatic lipogenesis in the genetic susceptibility to fatty liver were evaluated. These results showed that （1） the weight of fatty liver of the two breeds of geese were 801 and 375 g （P〈0.05）, respectively. There were no differences on the abdominal fat pat, filet total and filet pectoralis major in the two breeds experimental of the geese group （P〈0.05） and no difference on body and filet skin plus subcutaneous adipose tissue （P〉0.05） was found; （2） in these two breeds of geese, there were no differences on very-lowdensity lipoprotein （VLDL）, cholesteryl esters （CE） （P〈0.05）, free cholesterol （FC）, triglycerides （TG）, phospholipids （PL） and protein （P 〈 0.05）; （3） there were no differences on activities of malic enzyme （ME）, glucose-6-phosphatedehydrogenase （G6PDH）, acetyl-CoA-carboxylas （ACX）, fatty acid synthase （FAS）, and mRNA level of ME in the two experimental breeds of geese groups （P 〈0.05）; （4） test in Landaise geese group showed that there was no significant correlation with the specific enzymatic activities, while in Xupu geese group, the liver weight was negatively correlated to the specific activity of ACX and positively to that of ME; （5） in these overfed geese, ME activity appeared to be a major factor involved in the genetic susceptibility to hepatic steatosis and it determined the hepatic lipogenesis capacity.展开更多
Lipid metabolism and adipocyte differentiation are reglulated by networking of transcription factors. It is generally known that three factors, peroxisome proliferator-activated receptor y （PPARγ）, CCAAT/element-bi...Lipid metabolism and adipocyte differentiation are reglulated by networking of transcription factors. It is generally known that three factors, peroxisome proliferator-activated receptor y （PPARγ）, CCAAT/element-binding protein a （C/EBPa） and sterol regulatory element binding protein-1 （SREBP1）, play fundamental roles in metabolic pathways. And they are also important in adipocyte differentiation. Expressions of these factors are regulated by some compounds such as fatty acids or some steroid hormones （insulin） which is stimulated by the nutritional level. Furthermore, these factors are related to some metabolic diseases including type II diabetes and obesity, Lots of researches have focused on relationships between the factors and the genetic diseases. Different functions of factors on inducing the adipocyte differentiation are other hot spots according to previous studies. This paper summarized these studies and gave a limpid description of structures and functions of these genes.展开更多
The signal transduction network in regulating lipid metabolism is a hot topic of biomedical research. Recent research endeavors reveal that intracellular stress signaling from a cellular organelle called endoplasmic r...The signal transduction network in regulating lipid metabolism is a hot topic of biomedical research. Recent research endeavors reveal that intracellular stress signaling from a cellular organelle called endoplasmic reticulum (ER) is critically involved in lipid homeostasis and the development of metabolic disease. The ER is a site where newly-synthesized proteins are folded and assembled into their three-dimensional structures, modified and transported to their precise cellular destinations. A wide range of biochemical, physiological and pathological stimuli can interrupt the protein folding process in the ER and cause accumulation of unfolded or misfolded proteins in the ER lumen, a condition referred to as ER stress. To cope with this stress condition, the ER has evolved highly-specifi c signaling pathways collectively termed Unfolded Protein Response (UPR) or ER stress response. The UPR regulates transcriptionaland translational programs, affecting broad aspects of cellular metabolism and cell fate. Lipogenesis, the metabolic process of de novo lipid biosynthesis, occurs primarily in the liver where metabolic signals regulate expression of key enzymes in glycolytic and lipogenic pathways. Recent studies suggest that the UPR plays crucial roles in modulating lipogenesis under metabolic conditions. Here we address some of recent representative evidence regarding the role of the UPR in lipogenesis.展开更多
This study investigates if the anti-tumor effect of Pterostilbene in the SKOV3 ovarian cancer(OC)cell line involves inhibition of cell metabolism and tested in this effect involves modulating AMPK and Akt-induced regu...This study investigates if the anti-tumor effect of Pterostilbene in the SKOV3 ovarian cancer(OC)cell line involves inhibition of cell metabolism and tested in this effect involves modulating AMPK and Akt-induced regulation of mTORC1.Initially,SKOV3 cells were cultured in the humidified conditions in DMEM media for 24 h with or without increasing concentration of Pterostilbene.Then,the cells were incubated with Pterostilbene(IC_(50)=50μM)under similar conditions with or without pre-incubation with Dorsomorphin,an AMPK inhibitor.In a dose-dependent manner,Pterostilbene inhibited SKOV3 cell survival and increased their lysate levels of lactate dehydrogenase(LDH)and single-stranded DNA(ssDNA).When SKOV3 cells were treated with 50μM Pterostilbene,Pterostilbene significantly suppressed cell migration and invasion,reduced lysate levels of lactic acid and the optical density of Oil Red O staining,and increased lysate glucose levels.It also increased levels of malondialdehyde(MDA),reactive oxygen species(ROS),and induced intrinsic cell apoptosis by upregulating protein levels of Bax and cleaved caspase-3 and reducing protein levels of Bcl-2.Besides,Pterostilbene reduced mRNA levels of sterol regulatory element-binding protein 1(SREBP-1),fatty acid synthase(FAS),acetyl CoA carboxylase-1(ACC-1),and AMP-activated protein kinase(AMPK).Furthermore,Pterostilbene increased the protein levels of p-AMPK,p-p53,p-raptor,p-TSC-2,but significantly decreased protein levels of p-Akt,p-TSC-2,p-mTOR,p-S6K1,and p-4E-BP.Treatment with Dorsomorphin(CC)abolished all the anti-tumorigenesis effects afforded by Pterostilbene and prevented Pterostilbene-induced phosphorylation of Akt,p53,and mTOR.In conclusion,the tumorsuppressive effect of Pterostilbene in SKOV3 cells involves the induction of ROS and inhibition of dysregulation cell metabolism mainly due to AMPK-induced Akt-dependent or independent suppression of mTOR.展开更多
Aronia melamocarpa (AM) is a rich source of anthocyanins, which are known to help prevent obesity. The cyanidine-3-O-galactoside enriched AM extract (AM-Ex) containing more cyanidine-3-O-galactoside than conventional ...Aronia melamocarpa (AM) is a rich source of anthocyanins, which are known to help prevent obesity. The cyanidine-3-O-galactoside enriched AM extract (AM-Ex) containing more cyanidine-3-O-galactoside than conventional AM extract was recently developed. The objective of this study was to examine the effect of AM-Ex on adipogenesis and its action mechanisms in vitro using 3T3-L1 adipocytes. To examine the anti-obesity effect of AM-Ex, 3T3-L1 cells were induced adipocyte differentiation and incubated with various concentration of AM-Ex. Lipid accumulation, cellular triglyceride content, mRNA expression of transcription factors and adipogenic genes were analyzed. Treatment with 100 - 400 μg/mL of AM-Ex resulted in a dose-dependent decrease in adipocyte differentiation and triglyceride accumulation. mRNA expression of adipogenic transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein α, sterol regulatory element-binding protein 1 were decreased. The level of gene expression of adipogenesis and lipogenesis-related genes, such as adipocyte protein 2, lipoprotein lipase, acetyl-CoA carboxylase, ATP-citrate lyase and fatty acid synthase were decreased. These results suggest that AM-Ex alleviated risk factors related to obesity by modulating multiple pathways associated with adipogenesis.展开更多
Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often...Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.展开更多
Background:Our previous in vitro study has shown that total flavonoids from the leaves of Carya cathayensis exert estrogenic activities by promoting the expressions of ER𝛼and ER𝛽.C.cathayensis leaf ext...Background:Our previous in vitro study has shown that total flavonoids from the leaves of Carya cathayensis exert estrogenic activities by promoting the expressions of ER𝛼and ER𝛽.C.cathayensis leaf extract(CCE)was rich in flavonoids.Oral administration of CCE reduced the serum lipids and hepatic lipids,alleviated liver steatosis in ovariectomized rats.Objective:To investigate whether CCE has estrogenic effects on reproductive tissue and influences lipid metabolism in ovariectomized rats,and whether CCE has a direct effect on regulation of lipid synthesis and/or oxidation and adipocyte differentiation of ovariectomized(OVX)rats.Methods:Female Sprague-Dawley rats were ovariectomized and treated with CCE or estradiol in combination with a normal diet(ND),a high-fat diet(HFD)for 8 weeks.Histological analysis of uterus were performed and the lipid metabolism-related enzyme activity were examined.Expression of liver lipogenesis-related genes,adipocyte differentiation-and fat accumulation-related genes and protein were measured.Rusults:Ovariectomy accelerated the uterine atrophy,development of dyslipidemia and hepatic steatosis,which were effectively mitigated by CCE supplementation.CCE significantly elevated ovariectomy-induced reduction in the cross-section area of the uterus and uterine glands.Compared with the OVX group,CCE increased the activities of lipoprtein lipase(LPL)and hepatic lipase(HL),decreased the hepatic mRNA expressions of Fas,Srebf1,Sla2a2,and increased Ppar𝛼expressions at the mRNA levels under both ND and HFD conditions.CCE also decreased the Pck1 and G6pc mRNA expressions under HFD conditions,and show no significant effects on Hmgcr.The expressions of SREBF1,CEBPA and VEGF at the protein level were effectively regulated by CCE supplementation.Conclusion:CCE effectively alleviated ovariectomy-induced dyslipidemia and visceral fat accumulation by mod-ulating hepatic lipogenesis and adipocyte differentiation.Furthermore,CCE exhibited estrogenic activity for the prevention of postmenopausal fatty liver.展开更多
Non-alcoholic fatty liver disease(NAFLD)is characterized by the abnormal buildup of lipids in the liver tissue.Non-alcoholic fatty liver(NAFL)may progress to non-alcoholic steatohepatitis.Triglycerides in the liver ca...Non-alcoholic fatty liver disease(NAFLD)is characterized by the abnormal buildup of lipids in the liver tissue.Non-alcoholic fatty liver(NAFL)may progress to non-alcoholic steatohepatitis.Triglycerides in the liver can originate from various sources,including de novo lipogenesis(DNL).Research indicates that DNL significantly escalates in NAFLD,worsening steatosis.However,the precise regulatory mechanism of DNL in the development of this disease is not fully understood.Therefore,the targeted reduction of DNL could be a crucial therapeutic strategy.Currently,numerous pharmaceutical agents targeting DNL have been developed,attracting significant attention.This review examines the mechanism of DNL upregulation in NAFLD,assessing its potential as a therapeutic target for hepatic steatosis.Furthermore,we thoroughly examine hepatocellular lipotoxicity and provide an extensive review of the application and limitations of relevant therapeutic drugs,with a focus on key enzymes involved in DNL.The implementation of these pharmacological strategies is expected to significantly improve the management and overall outcomes for patients with NAFLD.展开更多
As a potential endocrine-disrupting chemical,bisphenol F(BPF)may cause nonalcoholic fatty liver disease(NAFLD)-like changes,but the mechanisms under its pathogenesis as well as the intervention strategies remain uncle...As a potential endocrine-disrupting chemical,bisphenol F(BPF)may cause nonalcoholic fatty liver disease(NAFLD)-like changes,but the mechanisms under its pathogenesis as well as the intervention strategies remain unclear.Using the electron microscopy technology,along with LipidTOX Deep Red neutral and Bodipy 493/503 staining assays,we observed that BPF treatment elicited a striking accumulation of lipid droplets in HepG2 cells,accompanied by an increased total level of triglycerides.At the molecular level,the lipogenesis-associated mRNAs and proteins,including acetyl-CoA carboxylase,fatty acid synthase,stearoyl-CoA desaturase-1,peroxisome proliferator-activated receptor gamma,and CCAAT-enhancer-binding proteins,increased significantly via the AMP-activated protein kinase(AMPK)-mammalian target of rapamycin(mTOR)signaling regulation in both in vitro and in vivo studies.Furthermore,the immunofluorescence results also showed the robust lipogenesis induced by BPF,evident in its ability to promote the translocation of sterol regulatory element-binding protein-1c from the cytoplasm to the nuclei.To investigate the intervention strategies for BPF-induced NAFLD-like changes,we demonstrated that bellidifolin,isolated and purified from Swertia chirayita,significantly attenuated BPF-induced lipid droplet deposition in HepG2 cells and NAFLD-like changes in mice by blocking the expression of lipogenesis-associated proteins.Therefore,the present study elucidates the mechanisms underlying the BPF-induced lipid accumulation in HepG2 cells,while also highlighting the potential of bellidifolin to mitigate BPF-induced NAFLD-like changes.展开更多
Background：A high consumption of fructose leads to hepatic steatosis.About 20-30% of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress （ERS） is involved in ...Background：A high consumption of fructose leads to hepatic steatosis.About 20-30% of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress （ERS） is involved in this process,while others showed that a lipotoxic environment directly influences ER homeostasis.Here,our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 （XBP-1）,one marker of ERS,on hepatic lipid accumulation stimulated by high fructose.Methods：HepG2 cells were incubated with different concentrations of fructose.Upstream regulators of de novo lipogenesis （i.e.,carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1 c [SREBP-lc]） were measured by polymerase chain reaction and key lipogenic enzymes （acetyl-CoA carboxylase [ACC],fatty acid synthase [FAS],and stearoyl-CoA desaturase-1 [SCD-1]） by Western blotting.The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid （TUDCA） or the ERS inducer thapsigargin.Finally,the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection.Results：Exposure to high fructose increased triglyceride levels in a dose-and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels ofFAS,ACC,and SCD-1,concomitant with XBP-1 conversion to an active spliced form.Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin.Triglyceride level in XBP-l-deficient group decreased significantly compared with high-fructose group （4.41 ± 0.54 μmol/g vs.6.52 ± 0.38 μmol/g,P 〈 0.001）,as mRNA expressions of SREBP-1c （2.92 ± 0.46 vs.5.08 ± 0.41,P 〈 0.01） and protein levels of FAS （0.53 ± 0.06 vs.0.85 ± 0.05,P =0.01）,SCD-1 （0.65 ± 0.06 vs.0.90 ± 0.04,P =0.04）,and ACC （0.38 ± 0.03 vs.0.95 ± 0.06,P 〈 0.01） decreased.Conversely,levels of triglyceride （4.22 ± 0.54 μmol/g vs.2.41 ± 0.35 μmol/g,P 〈 0.001）,mRNA expression of SREBP-1c （2.70 ± 0.33 vs.1.00 ± 0.00,P 〈 0.0 1）,and protein expression of SCD-1 （0.93 ± 0.06 vs.0.26 ± 0.05,P 〈 0.01）,ACC （0.98 ± 0.09 vs.0.43 ± 0.03,P 〈 0.01）,and FAS （0.90 ± 0.33 vs.0.71 ±4 0.02,P =0.04） in XBP-ls-upregulated group increased compared with the untransfected group.Conclusions：ERS is associated with de novo lipogenesis,and XBP-1 partially mediates high-fructose-induced lipid accumulation in HepG2 cells through augmentation of de novo lipogenesis.展开更多
Incubating plasma membranes prepared from pig liver with varying concentrations of insulin (50—1000 μU/ml) resulted in the release of at least two insulin chemical mediators. One of them was fraction 1 of insulin me...Incubating plasma membranes prepared from pig liver with varying concentrations of insulin (50—1000 μU/ml) resulted in the release of at least two insulin chemical mediators. One of them was fraction 1 of insulin mediator (M. W. 3700—4000 daltons) which had a significant lipogenesis-stimulatlug activity. The other was fraction 2 of insulin mediator (M. W. about 1000 daltons) which exhibited a lipogenesis-inhibitory activity.The ratio of yield between the two mediators produced from the membranes was not only dependent on the concentration but also on the potency of insulin and its analogs added. The result showed that there was more production of fraction 2 than fraction 1 with the inducer at low concentration (100 μU/ml), while the production of fraction 1 from the plasma membranes incubated with high concentration of insulin (300 μU/ml) was higher than fraction 2. On the other hand, insulin and its analogs which have different biological activities and receptor bindtng activities have been used to induce the insulin mediators. The results obtained were similar to those mentioned above. This suggested that the generation of the mediators was dependent on the biological potences but not the binding activities.展开更多
The liver is a vital organ in chickens that performs a number of crucial physiological functions, including the storage of hepatic glycogen, protein synthesis, detoxification, and deoxidation. The growth and metabolis...The liver is a vital organ in chickens that performs a number of crucial physiological functions, including the storage of hepatic glycogen, protein synthesis, detoxification, and deoxidation. The growth and metabolism of the liver are complex processes influenced by factors such as environment, diet, and genetics. MicroRNAs(miRNAs), as posttranscriptional regulatory molecules, play a role in various biological processes. There is growing evidence that miR-27b-5p plays a key role in the regulation of liver development and metabolism in various species. However, its role in chicken livers has yet to be determined. In our experiment, we found that chickens with fatty livers had significantly higher levels of serum triglyceride(TG) and total cholesterol(TC) compared to the normal chickens, while the control group had significantly higher levels of very low-density lipoprotein(VLDL) and serum hormones. Further research showed that the mRNA of miR-27b-5p was highly expressed in fatty livers. By exploring the function of miR-27b-5p in chicken livers, we discovered that it promotes lipogenesis, oxidative stress, and inflammatory responses, leading to hepatocyte apoptosis. Our study also established the mechanism by which miR-27b-5p interacts with its target gene, and found that miR-27b-5p targets insulin receptor substrate 2(IRS2) and modulates the PI3K/AKT signaling pathway. Additionally, our investigation of IRS2 in chicken hepatocytes revealed that knocking down IRS2 has the same effects as overexpressing miR-27b-5p. In conclusion, our study revealed that miR-27b-5p directly binds to IRS2, inhibiting the PI3K/AKT signaling pathway and causing steatosis, oxidative stress, inflammation, and apoptosis in chicken liver.展开更多
Background Dietary fat is important for energy provision and immune function of lactating sows and their progeny.However,knowledge on the impact of fat on mammary transcription of lipogenic genes,de novo fat synthesis...Background Dietary fat is important for energy provision and immune function of lactating sows and their progeny.However,knowledge on the impact of fat on mammary transcription of lipogenic genes,de novo fat synthesis,and milk fatty acid(FA)output is sparse in sows.This study aimed to evaluate impacts of dietary fat levels and FA composition on these traits in sows.Forty second-parity sows(Danish Landrace×Yorkshire)were assigned to 1 of 5 dietary treatments from d 108 of gestation until weaning(d 28 of lactation):low-fat control diet(3%added animal fat);or 1 of 4 high-fat diets with 8%added fat:coconut oil(CO),fish oil(FO),sunflower oil(SO),or 4%octanoic acid plus 4%FO(OFO).Three approaches were taken to estimate de novo milk fat synthesis from glucose and body fat.Results Daily intake of FA was lowest in low-fat sows within fat levels(P<0.01)and in OFO and FO sows within highfat diets(P<0.01).Daily milk outputs of fat,FA,energy,and FA-derived carbon reflected to a large extent the intake of those.On average,estimates for de novo fat synthesis were 82 or 194 g/d from glucose according to method 1 or 2 and 255 g de novo+mobilized FA/d according to method 3.The low-fat diet increased mammary FAS expression(P<0.05)and de novo fat synthesis(method 1;P=0.13)within fat levels.The OFO diet increased de novo fat synthesis(method 1;P<0.05)and numerically upregulated mammary FAS expression compared to the other high-fat diets.Across diets,a daily intake of 440 g digestible FA minimized milk fat originating from glucose and mobilized body fat.Conclusions Sows fed diets with low-fat or octanoic acid,through upregulating FAS expression,increased mammary de novo fat synthesis whereas the milk FA output remained low in sows fed the low-fat diet or high-fat OFO or FO diets,indicating that dietary FA intake,dietary fat level,and body fat mobilization in concert determine de novo fat synthesis,amount and profiles of FA in milk.展开更多
The impacts of dexamethasone(Dex)and thyroid hormone T3 on the insulin-stimulated Srebp-1c expression were studied in primary rat hepatocytes. Primary hepatocytes from Sprague-Dawley rats were isolated, cultured and t...The impacts of dexamethasone(Dex)and thyroid hormone T3 on the insulin-stimulated Srebp-1c expression were studied in primary rat hepatocytes. Primary hepatocytes from Sprague-Dawley rats were isolated, cultured and treated with insulin in the presence or absence of the indicated reagents over time. The mRNA levels of indicated genes were determined using real-time PCR. Insulin treatment induced the Srebp-1c expression and suppressed the Pck1 expression in a time-dependent manner. Dex treatment alone reduced the Srebp-1c expression, whereas potentiated the insulin-induced its expression, which reached to a level that was higher than the insulin alone group. On the other hand, insulin treatment completely suppressed the Dex-induced Pck1 expression in the same cells. T3 treatment did not affect the expressions of Srebp-1c and Pck1 alone or in the presence of absence of insulin or Dex. Interestingly, insulin treatment induced the Rxrg m RNA expression level in the absence or presence of T0901317, a specific agonist for the liver X receptor. Dex and insulin mutually affect each other's ability to regulate the expression levels of hepatic genes involved in glucose and fatty acid metabolism. Insulin induced Rxrg expression in primary hepatocytes, which may contribute to the induction of Srebp-1c expression in the same cells.展开更多
Objective:To investigate the relationship between SREBP1 protein expression and clinicopathological features of hepatitis B virus infection-related hepatocellular carcinoma.Methods:A total of 91 cases of hepatocellula...Objective:To investigate the relationship between SREBP1 protein expression and clinicopathological features of hepatitis B virus infection-related hepatocellular carcinoma.Methods:A total of 91 cases of hepatocellular carcinoma associated with hepatitis B virus infection and paired adjacent liver tissue samples were collected from the Department of Pathology,the First Affiliated Hospital of Hainan Medical College.The expression of SREBP1 protein in cancer and paired adjacent tissues was detected by immunohistochemical staining.The relationship between SREBP1 protein expression and clinicopathological features of hepatocellular carcinoma was analyzed by chi-square test.Results:The results of immunohistochemical staining showed that the ex-pression of SREBP1 protein in hepatocellular carcinoma was significantly higher than that in adjacent liver tissues(P<0.001).The expression level of SREBP1 protein was significantly correlated with tumor differentiation,distant metastasis or local recurrence in patients with hepatocellular carcinoma(P<0.05).The expression of SREBP1 protein was significantly up-regulated in the high HBV-related HCC virus load group(>103 IU/mL)compared with the low HBV-related HCC virus load group 3(0~10 IU/mL)(P<0.05).Conclusion:1.The expression of SREBP1 protein is correlated with hepatocellular carcinoma,and shows a high expression trend,which provides direction and theoretical basis for the study of lipid metabolism regulation mechnism related to the occurrence and development of hepatocellular carcinoma.2.The expression of SREBP1 protein is correlated with the replication activity of hepatitis B virus,which provides a new research direction for the exploration of the mechanism of the occurrence and development of hepatitis B virus infection-related liver cancer.展开更多
Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease(NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors(PPARs) are transcr...Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease(NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors(PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation(mitochondrial and peroxisomal)and microsomal omega-oxidation, being markedly decreased by high-fat(HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.展开更多
Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the tr...Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols(i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids(i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates(i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.展开更多
基金supported by the National Key Research and Development Program,China (2022YFF1000300 to Z.Y.and2022YFD2401800 to G.Z.)Pilot Program A Project from the Chinese Academy of Sciences (XDA24010206 to Z.Y.)+3 种基金Foundation of Hubei Hongshan Laboratory (2021hskf013 to G.Z.and 2021hszd021 to Z.Y.)National Natural Science Foundation of China (31972779 to G.Z.)Youth Innovation Promotion Association of CAS (2020336 to G.Z.)State Key Laboratory of Freshwater Ecology and Biotechnology (2016FBZ05 to Z.Y.)。
文摘Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males.However,the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood,especially in teleosts.In this study,cyp17a1-/-zebrafish(Danio rerio)exhibited excessive visceral adipose tissue(VAT),lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis(DNL)enzymes.The assay for transposase accessible chromatinwithsequencing(ATAC-seq)results demonstrated that chromatin accessibility of DNL genes was increased in cyp17a1-/-fish compared to cyp17a1+/+male fish,including stearoyl-CoA desaturase(scd)and fatty acid synthase(fasn).Androgen response element(ARE)motifs in the androgen signaling pathway were significantly enriched in cyp17a1+/+male fish but not in cyp17a1-/-fish.Both androgen receptor(ar)-/-and wildtype(WT)zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue,lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis enzymes.The Ar agonist BMS-564929 reduced the content of VAT and lipid content,and down-regulated acetyl-CoA carboxylase a(acaca),fasn,and scd expression.Mechanistically,the rescue effect of testosterone on cyp17a1-/-fish in terms of phenotypes was abolished when ar was additionally depleted.Collectively,these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish,thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.
文摘Although significant advances have been made in understanding the pathophysiology of psychiatric disorders(PDs),therapeutic advances have not been very convincing.While psychotropic medications can reduce classical symptoms in patients with PDs,their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes,obesity and non-alcoholic fatty liver disease(NAFLD).The mechanism(s)underlying these metabolic abnormalities is not clear;however,lipid/fatty acid accumulation due to enhanced de novo lipogenesis(DNL)has been shown to reduce membrane fluidity,increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities.Intriguingly,emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity,diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs.In support of this,several adjunctive drugs comprising of anti-oxidants and antiinflammatory agents,that are used in treating PDs in combination with psychotropic medications,have been shown to reduce insulin resistance and development of NAFLD.In conclusion,the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities,and a new avenue for translational research and therapeutic drug designing in PDs.
文摘Hatchery-roared juvenile black sea breams are characterized by a low level of highly unsaturated fatty acids in their bodies, as compared with wild fish. To assess the effect of docosahaxaenoic acid （DHA） on lipegenic and lipelysis enzymes, one-year fish were roared on a casein-based purified diet and a DHA fortified diet （ 1.5% DHA ethyl ester/kg diet） for 60 d, followed with a period of 55 d for starvation. Dietary DHA was effectively incorporated into the fish body. Fortification of DHA depressed activities of glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase as lipogenic enzymes in the hepatopancroas and intraperitoneal fat body. Carnitine palmitoyltransferase as lipolysis enzyme in the hepatopancreas was active in the DHA fortified fish. Starvation after feeding experiment induced increased carnitine palmitoyltransferase activity in both control and DHA fortified fish and the activity remained higher in the DHA fortified fish, while the monoenes were selectively consumed prior to highly unsaturated fatty acids. These results indicated that dietary DHA depressed lipogenesis and activated lipolysis.
文摘This experiment studied hepatic lipogenesis associated with biochemical changes in overfed Landaise Geese and China Xupu geese. Twenty healthy male Landaise geese and 20 healthy male Xupu geese, hatched on the same day under the same feeding conditions, were selected as experimental animals. The animals were divided into two groups and each breed served as an experimental group. Per goose of per experimental group served for a repeat. Brown rice was selected as test diet. After overfeeding for 21 d and then slaughtering, the biochemical changes of hepatic lipogenesis in the genetic susceptibility to fatty liver were evaluated. These results showed that （1） the weight of fatty liver of the two breeds of geese were 801 and 375 g （P〈0.05）, respectively. There were no differences on the abdominal fat pat, filet total and filet pectoralis major in the two breeds experimental of the geese group （P〈0.05） and no difference on body and filet skin plus subcutaneous adipose tissue （P〉0.05） was found; （2） in these two breeds of geese, there were no differences on very-lowdensity lipoprotein （VLDL）, cholesteryl esters （CE） （P〈0.05）, free cholesterol （FC）, triglycerides （TG）, phospholipids （PL） and protein （P 〈 0.05）; （3） there were no differences on activities of malic enzyme （ME）, glucose-6-phosphatedehydrogenase （G6PDH）, acetyl-CoA-carboxylas （ACX）, fatty acid synthase （FAS）, and mRNA level of ME in the two experimental breeds of geese groups （P 〈0.05）; （4） test in Landaise geese group showed that there was no significant correlation with the specific enzymatic activities, while in Xupu geese group, the liver weight was negatively correlated to the specific activity of ACX and positively to that of ME; （5） in these overfed geese, ME activity appeared to be a major factor involved in the genetic susceptibility to hepatic steatosis and it determined the hepatic lipogenesis capacity.
基金Supported by National Natural Science Foundation Key Project of China(30430510)Natural Science Foundation Key Project of Heilongjiang Province(ZJN0604-01)National 973 Project of China(2006CB102105)
文摘Lipid metabolism and adipocyte differentiation are reglulated by networking of transcription factors. It is generally known that three factors, peroxisome proliferator-activated receptor y （PPARγ）, CCAAT/element-binding protein a （C/EBPa） and sterol regulatory element binding protein-1 （SREBP1）, play fundamental roles in metabolic pathways. And they are also important in adipocyte differentiation. Expressions of these factors are regulated by some compounds such as fatty acids or some steroid hormones （insulin） which is stimulated by the nutritional level. Furthermore, these factors are related to some metabolic diseases including type II diabetes and obesity, Lots of researches have focused on relationships between the factors and the genetic diseases. Different functions of factors on inducing the adipocyte differentiation are other hot spots according to previous studies. This paper summarized these studies and gave a limpid description of structures and functions of these genes.
基金Supported partially by the American Heart Association (AHA) Scientist Development Award (0635423Z)the AHA Grant-in-Aid (09GRNT2280479)+1 种基金the Department of Defense Breast Cancer Research Program (BC095179P1)the Karmanos Cancer Institute Pilot Grant
文摘The signal transduction network in regulating lipid metabolism is a hot topic of biomedical research. Recent research endeavors reveal that intracellular stress signaling from a cellular organelle called endoplasmic reticulum (ER) is critically involved in lipid homeostasis and the development of metabolic disease. The ER is a site where newly-synthesized proteins are folded and assembled into their three-dimensional structures, modified and transported to their precise cellular destinations. A wide range of biochemical, physiological and pathological stimuli can interrupt the protein folding process in the ER and cause accumulation of unfolded or misfolded proteins in the ER lumen, a condition referred to as ER stress. To cope with this stress condition, the ER has evolved highly-specifi c signaling pathways collectively termed Unfolded Protein Response (UPR) or ER stress response. The UPR regulates transcriptionaland translational programs, affecting broad aspects of cellular metabolism and cell fate. Lipogenesis, the metabolic process of de novo lipid biosynthesis, occurs primarily in the liver where metabolic signals regulate expression of key enzymes in glycolytic and lipogenic pathways. Recent studies suggest that the UPR plays crucial roles in modulating lipogenesis under metabolic conditions. Here we address some of recent representative evidence regarding the role of the UPR in lipogenesis.
基金supported by the Deputyship for Research&Innovation,Ministry of Education in Saudi Arabia for funding this research work through the project number PNU-DRI-RI-20-012.
文摘This study investigates if the anti-tumor effect of Pterostilbene in the SKOV3 ovarian cancer(OC)cell line involves inhibition of cell metabolism and tested in this effect involves modulating AMPK and Akt-induced regulation of mTORC1.Initially,SKOV3 cells were cultured in the humidified conditions in DMEM media for 24 h with or without increasing concentration of Pterostilbene.Then,the cells were incubated with Pterostilbene(IC_(50)=50μM)under similar conditions with or without pre-incubation with Dorsomorphin,an AMPK inhibitor.In a dose-dependent manner,Pterostilbene inhibited SKOV3 cell survival and increased their lysate levels of lactate dehydrogenase(LDH)and single-stranded DNA(ssDNA).When SKOV3 cells were treated with 50μM Pterostilbene,Pterostilbene significantly suppressed cell migration and invasion,reduced lysate levels of lactic acid and the optical density of Oil Red O staining,and increased lysate glucose levels.It also increased levels of malondialdehyde(MDA),reactive oxygen species(ROS),and induced intrinsic cell apoptosis by upregulating protein levels of Bax and cleaved caspase-3 and reducing protein levels of Bcl-2.Besides,Pterostilbene reduced mRNA levels of sterol regulatory element-binding protein 1(SREBP-1),fatty acid synthase(FAS),acetyl CoA carboxylase-1(ACC-1),and AMP-activated protein kinase(AMPK).Furthermore,Pterostilbene increased the protein levels of p-AMPK,p-p53,p-raptor,p-TSC-2,but significantly decreased protein levels of p-Akt,p-TSC-2,p-mTOR,p-S6K1,and p-4E-BP.Treatment with Dorsomorphin(CC)abolished all the anti-tumorigenesis effects afforded by Pterostilbene and prevented Pterostilbene-induced phosphorylation of Akt,p53,and mTOR.In conclusion,the tumorsuppressive effect of Pterostilbene in SKOV3 cells involves the induction of ROS and inhibition of dysregulation cell metabolism mainly due to AMPK-induced Akt-dependent or independent suppression of mTOR.
文摘Aronia melamocarpa (AM) is a rich source of anthocyanins, which are known to help prevent obesity. The cyanidine-3-O-galactoside enriched AM extract (AM-Ex) containing more cyanidine-3-O-galactoside than conventional AM extract was recently developed. The objective of this study was to examine the effect of AM-Ex on adipogenesis and its action mechanisms in vitro using 3T3-L1 adipocytes. To examine the anti-obesity effect of AM-Ex, 3T3-L1 cells were induced adipocyte differentiation and incubated with various concentration of AM-Ex. Lipid accumulation, cellular triglyceride content, mRNA expression of transcription factors and adipogenic genes were analyzed. Treatment with 100 - 400 μg/mL of AM-Ex resulted in a dose-dependent decrease in adipocyte differentiation and triglyceride accumulation. mRNA expression of adipogenic transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein α, sterol regulatory element-binding protein 1 were decreased. The level of gene expression of adipogenesis and lipogenesis-related genes, such as adipocyte protein 2, lipoprotein lipase, acetyl-CoA carboxylase, ATP-citrate lyase and fatty acid synthase were decreased. These results suggest that AM-Ex alleviated risk factors related to obesity by modulating multiple pathways associated with adipogenesis.
基金supported by the National Natural Science Foundation of China(32171381 and 81973254)the National Innovation of Science and Technology-2030(Program of Brain Science and Brain-Inspired Intelligence Technology)grant(2021ZD0204004,China)+1 种基金Jiangsu Key Laboratory of Neuropsychiatric Diseases Research Major Program(No.ZZ2101,China)the Priority Academic Program Development of the Jiangsu Higher Education Institutes(PAPD),Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases,and the Suzhou Science and Technology Development Project(No.SJC2022021,China).
文摘Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.
基金This project was financially supported by the Natural Science Foun-dation of China(Grant No:81303258).
文摘Background:Our previous in vitro study has shown that total flavonoids from the leaves of Carya cathayensis exert estrogenic activities by promoting the expressions of ER𝛼and ER𝛽.C.cathayensis leaf extract(CCE)was rich in flavonoids.Oral administration of CCE reduced the serum lipids and hepatic lipids,alleviated liver steatosis in ovariectomized rats.Objective:To investigate whether CCE has estrogenic effects on reproductive tissue and influences lipid metabolism in ovariectomized rats,and whether CCE has a direct effect on regulation of lipid synthesis and/or oxidation and adipocyte differentiation of ovariectomized(OVX)rats.Methods:Female Sprague-Dawley rats were ovariectomized and treated with CCE or estradiol in combination with a normal diet(ND),a high-fat diet(HFD)for 8 weeks.Histological analysis of uterus were performed and the lipid metabolism-related enzyme activity were examined.Expression of liver lipogenesis-related genes,adipocyte differentiation-and fat accumulation-related genes and protein were measured.Rusults:Ovariectomy accelerated the uterine atrophy,development of dyslipidemia and hepatic steatosis,which were effectively mitigated by CCE supplementation.CCE significantly elevated ovariectomy-induced reduction in the cross-section area of the uterus and uterine glands.Compared with the OVX group,CCE increased the activities of lipoprtein lipase(LPL)and hepatic lipase(HL),decreased the hepatic mRNA expressions of Fas,Srebf1,Sla2a2,and increased Ppar𝛼expressions at the mRNA levels under both ND and HFD conditions.CCE also decreased the Pck1 and G6pc mRNA expressions under HFD conditions,and show no significant effects on Hmgcr.The expressions of SREBF1,CEBPA and VEGF at the protein level were effectively regulated by CCE supplementation.Conclusion:CCE effectively alleviated ovariectomy-induced dyslipidemia and visceral fat accumulation by mod-ulating hepatic lipogenesis and adipocyte differentiation.Furthermore,CCE exhibited estrogenic activity for the prevention of postmenopausal fatty liver.
基金the National Natural Science Foundation of China(82325008).
文摘Non-alcoholic fatty liver disease(NAFLD)is characterized by the abnormal buildup of lipids in the liver tissue.Non-alcoholic fatty liver(NAFL)may progress to non-alcoholic steatohepatitis.Triglycerides in the liver can originate from various sources,including de novo lipogenesis(DNL).Research indicates that DNL significantly escalates in NAFLD,worsening steatosis.However,the precise regulatory mechanism of DNL in the development of this disease is not fully understood.Therefore,the targeted reduction of DNL could be a crucial therapeutic strategy.Currently,numerous pharmaceutical agents targeting DNL have been developed,attracting significant attention.This review examines the mechanism of DNL upregulation in NAFLD,assessing its potential as a therapeutic target for hepatic steatosis.Furthermore,we thoroughly examine hepatocellular lipotoxicity and provide an extensive review of the application and limitations of relevant therapeutic drugs,with a focus on key enzymes involved in DNL.The implementation of these pharmacological strategies is expected to significantly improve the management and overall outcomes for patients with NAFLD.
基金supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.21KJA330002)Natural Science Foundation of Jiangsu Province(Grant No.BK20211252)+3 种基金Young and Middle-aged Academic Leaders of the"Blue Project"in Jiangsu Universities(2022-2)Jiangsu Health and Family Planning Commission Medical Research Program(Grant No.Z2018035)Project of Public Health Research Center of Jiangnan University(Grant No.JUPH201842)Natural Science Foundation of Nanjing University of Chinese Medicine(Grant No.XZR2020021).
文摘As a potential endocrine-disrupting chemical,bisphenol F(BPF)may cause nonalcoholic fatty liver disease(NAFLD)-like changes,but the mechanisms under its pathogenesis as well as the intervention strategies remain unclear.Using the electron microscopy technology,along with LipidTOX Deep Red neutral and Bodipy 493/503 staining assays,we observed that BPF treatment elicited a striking accumulation of lipid droplets in HepG2 cells,accompanied by an increased total level of triglycerides.At the molecular level,the lipogenesis-associated mRNAs and proteins,including acetyl-CoA carboxylase,fatty acid synthase,stearoyl-CoA desaturase-1,peroxisome proliferator-activated receptor gamma,and CCAAT-enhancer-binding proteins,increased significantly via the AMP-activated protein kinase(AMPK)-mammalian target of rapamycin(mTOR)signaling regulation in both in vitro and in vivo studies.Furthermore,the immunofluorescence results also showed the robust lipogenesis induced by BPF,evident in its ability to promote the translocation of sterol regulatory element-binding protein-1c from the cytoplasm to the nuclei.To investigate the intervention strategies for BPF-induced NAFLD-like changes,we demonstrated that bellidifolin,isolated and purified from Swertia chirayita,significantly attenuated BPF-induced lipid droplet deposition in HepG2 cells and NAFLD-like changes in mice by blocking the expression of lipogenesis-associated proteins.Therefore,the present study elucidates the mechanisms underlying the BPF-induced lipid accumulation in HepG2 cells,while also highlighting the potential of bellidifolin to mitigate BPF-induced NAFLD-like changes.
文摘Background：A high consumption of fructose leads to hepatic steatosis.About 20-30% of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress （ERS） is involved in this process,while others showed that a lipotoxic environment directly influences ER homeostasis.Here,our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 （XBP-1）,one marker of ERS,on hepatic lipid accumulation stimulated by high fructose.Methods：HepG2 cells were incubated with different concentrations of fructose.Upstream regulators of de novo lipogenesis （i.e.,carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1 c [SREBP-lc]） were measured by polymerase chain reaction and key lipogenic enzymes （acetyl-CoA carboxylase [ACC],fatty acid synthase [FAS],and stearoyl-CoA desaturase-1 [SCD-1]） by Western blotting.The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid （TUDCA） or the ERS inducer thapsigargin.Finally,the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection.Results：Exposure to high fructose increased triglyceride levels in a dose-and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels ofFAS,ACC,and SCD-1,concomitant with XBP-1 conversion to an active spliced form.Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin.Triglyceride level in XBP-l-deficient group decreased significantly compared with high-fructose group （4.41 ± 0.54 μmol/g vs.6.52 ± 0.38 μmol/g,P 〈 0.001）,as mRNA expressions of SREBP-1c （2.92 ± 0.46 vs.5.08 ± 0.41,P 〈 0.01） and protein levels of FAS （0.53 ± 0.06 vs.0.85 ± 0.05,P =0.01）,SCD-1 （0.65 ± 0.06 vs.0.90 ± 0.04,P =0.04）,and ACC （0.38 ± 0.03 vs.0.95 ± 0.06,P 〈 0.01） decreased.Conversely,levels of triglyceride （4.22 ± 0.54 μmol/g vs.2.41 ± 0.35 μmol/g,P 〈 0.001）,mRNA expression of SREBP-1c （2.70 ± 0.33 vs.1.00 ± 0.00,P 〈 0.0 1）,and protein expression of SCD-1 （0.93 ± 0.06 vs.0.26 ± 0.05,P 〈 0.01）,ACC （0.98 ± 0.09 vs.0.43 ± 0.03,P 〈 0.01）,and FAS （0.90 ± 0.33 vs.0.71 ±4 0.02,P =0.04） in XBP-ls-upregulated group increased compared with the untransfected group.Conclusions：ERS is associated with de novo lipogenesis,and XBP-1 partially mediates high-fructose-induced lipid accumulation in HepG2 cells through augmentation of de novo lipogenesis.
基金Project supported by the National Natural Science Foundation of China.
文摘Incubating plasma membranes prepared from pig liver with varying concentrations of insulin (50—1000 μU/ml) resulted in the release of at least two insulin chemical mediators. One of them was fraction 1 of insulin mediator (M. W. 3700—4000 daltons) which had a significant lipogenesis-stimulatlug activity. The other was fraction 2 of insulin mediator (M. W. about 1000 daltons) which exhibited a lipogenesis-inhibitory activity.The ratio of yield between the two mediators produced from the membranes was not only dependent on the concentration but also on the potency of insulin and its analogs added. The result showed that there was more production of fraction 2 than fraction 1 with the inducer at low concentration (100 μU/ml), while the production of fraction 1 from the plasma membranes incubated with high concentration of insulin (300 μU/ml) was higher than fraction 2. On the other hand, insulin and its analogs which have different biological activities and receptor bindtng activities have been used to induce the insulin mediators. The results obtained were similar to those mentioned above. This suggested that the generation of the mediators was dependent on the biological potences but not the binding activities.
基金financially supported by the National Key Research and Development Program of China (2021YFD1300600)the Sichuan Science and Technology Program, China (2021YFYZ0007 and 2022YFYZ0005)the China Agriculture Research System of MOF and MARA (CARS-40-K06)。
文摘The liver is a vital organ in chickens that performs a number of crucial physiological functions, including the storage of hepatic glycogen, protein synthesis, detoxification, and deoxidation. The growth and metabolism of the liver are complex processes influenced by factors such as environment, diet, and genetics. MicroRNAs(miRNAs), as posttranscriptional regulatory molecules, play a role in various biological processes. There is growing evidence that miR-27b-5p plays a key role in the regulation of liver development and metabolism in various species. However, its role in chicken livers has yet to be determined. In our experiment, we found that chickens with fatty livers had significantly higher levels of serum triglyceride(TG) and total cholesterol(TC) compared to the normal chickens, while the control group had significantly higher levels of very low-density lipoprotein(VLDL) and serum hormones. Further research showed that the mRNA of miR-27b-5p was highly expressed in fatty livers. By exploring the function of miR-27b-5p in chicken livers, we discovered that it promotes lipogenesis, oxidative stress, and inflammatory responses, leading to hepatocyte apoptosis. Our study also established the mechanism by which miR-27b-5p interacts with its target gene, and found that miR-27b-5p targets insulin receptor substrate 2(IRS2) and modulates the PI3K/AKT signaling pathway. Additionally, our investigation of IRS2 in chicken hepatocytes revealed that knocking down IRS2 has the same effects as overexpressing miR-27b-5p. In conclusion, our study revealed that miR-27b-5p directly binds to IRS2, inhibiting the PI3K/AKT signaling pathway and causing steatosis, oxidative stress, inflammation, and apoptosis in chicken liver.
基金Financially supported by the Danish Council for Independent Research,Technology and Production Sciences (Copenhagen K,Denmark)。
文摘Background Dietary fat is important for energy provision and immune function of lactating sows and their progeny.However,knowledge on the impact of fat on mammary transcription of lipogenic genes,de novo fat synthesis,and milk fatty acid(FA)output is sparse in sows.This study aimed to evaluate impacts of dietary fat levels and FA composition on these traits in sows.Forty second-parity sows(Danish Landrace×Yorkshire)were assigned to 1 of 5 dietary treatments from d 108 of gestation until weaning(d 28 of lactation):low-fat control diet(3%added animal fat);or 1 of 4 high-fat diets with 8%added fat:coconut oil(CO),fish oil(FO),sunflower oil(SO),or 4%octanoic acid plus 4%FO(OFO).Three approaches were taken to estimate de novo milk fat synthesis from glucose and body fat.Results Daily intake of FA was lowest in low-fat sows within fat levels(P<0.01)and in OFO and FO sows within highfat diets(P<0.01).Daily milk outputs of fat,FA,energy,and FA-derived carbon reflected to a large extent the intake of those.On average,estimates for de novo fat synthesis were 82 or 194 g/d from glucose according to method 1 or 2 and 255 g de novo+mobilized FA/d according to method 3.The low-fat diet increased mammary FAS expression(P<0.05)and de novo fat synthesis(method 1;P=0.13)within fat levels.The OFO diet increased de novo fat synthesis(method 1;P<0.05)and numerically upregulated mammary FAS expression compared to the other high-fat diets.Across diets,a daily intake of 440 g digestible FA minimized milk fat originating from glucose and mobilized body fat.Conclusions Sows fed diets with low-fat or octanoic acid,through upregulating FAS expression,increased mammary de novo fat synthesis whereas the milk FA output remained low in sows fed the low-fat diet or high-fat OFO or FO diets,indicating that dietary FA intake,dietary fat level,and body fat mobilization in concert determine de novo fat synthesis,amount and profiles of FA in milk.
基金the Scientific Research Project of Wuhan Municipal Health Commission for research support to Y. Zhang (WX19Y09)。
文摘The impacts of dexamethasone(Dex)and thyroid hormone T3 on the insulin-stimulated Srebp-1c expression were studied in primary rat hepatocytes. Primary hepatocytes from Sprague-Dawley rats were isolated, cultured and treated with insulin in the presence or absence of the indicated reagents over time. The mRNA levels of indicated genes were determined using real-time PCR. Insulin treatment induced the Srebp-1c expression and suppressed the Pck1 expression in a time-dependent manner. Dex treatment alone reduced the Srebp-1c expression, whereas potentiated the insulin-induced its expression, which reached to a level that was higher than the insulin alone group. On the other hand, insulin treatment completely suppressed the Dex-induced Pck1 expression in the same cells. T3 treatment did not affect the expressions of Srebp-1c and Pck1 alone or in the presence of absence of insulin or Dex. Interestingly, insulin treatment induced the Rxrg m RNA expression level in the absence or presence of T0901317, a specific agonist for the liver X receptor. Dex and insulin mutually affect each other's ability to regulate the expression levels of hepatic genes involved in glucose and fatty acid metabolism. Insulin induced Rxrg expression in primary hepatocytes, which may contribute to the induction of Srebp-1c expression in the same cells.
基金Natural Science Foundation of Hainan Province(No.820RC763)。
文摘Objective:To investigate the relationship between SREBP1 protein expression and clinicopathological features of hepatitis B virus infection-related hepatocellular carcinoma.Methods:A total of 91 cases of hepatocellular carcinoma associated with hepatitis B virus infection and paired adjacent liver tissue samples were collected from the Department of Pathology,the First Affiliated Hospital of Hainan Medical College.The expression of SREBP1 protein in cancer and paired adjacent tissues was detected by immunohistochemical staining.The relationship between SREBP1 protein expression and clinicopathological features of hepatocellular carcinoma was analyzed by chi-square test.Results:The results of immunohistochemical staining showed that the ex-pression of SREBP1 protein in hepatocellular carcinoma was significantly higher than that in adjacent liver tissues(P<0.001).The expression level of SREBP1 protein was significantly correlated with tumor differentiation,distant metastasis or local recurrence in patients with hepatocellular carcinoma(P<0.05).The expression of SREBP1 protein was significantly up-regulated in the high HBV-related HCC virus load group(>103 IU/mL)compared with the low HBV-related HCC virus load group 3(0~10 IU/mL)(P<0.05).Conclusion:1.The expression of SREBP1 protein is correlated with hepatocellular carcinoma,and shows a high expression trend,which provides direction and theoretical basis for the study of lipid metabolism regulation mechnism related to the occurrence and development of hepatocellular carcinoma.2.The expression of SREBP1 protein is correlated with the replication activity of hepatitis B virus,which provides a new research direction for the exploration of the mechanism of the occurrence and development of hepatitis B virus infection-related liver cancer.
文摘Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease(NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors(PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation(mitochondrial and peroxisomal)and microsomal omega-oxidation, being markedly decreased by high-fat(HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.
文摘Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols(i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids(i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates(i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.
