BACKGROUND Allyl isothiocyanate(AITC),a classic anti-inflammatory and antitumorigenic agent,was recently identified as a potential treatment for obesity and insulin resistance.However,little is known about its direct ...BACKGROUND Allyl isothiocyanate(AITC),a classic anti-inflammatory and antitumorigenic agent,was recently identified as a potential treatment for obesity and insulin resistance.However,little is known about its direct impact on the liver.AIM To investigate the effect and underlying mechanism of AITC in nonalcoholic fatty liver disease(commonly referred to as NAFLD).METHODS To establish a mouse and cellular model of NAFLD,C57BL/6 mice were fed a high fat diet(HFD)for 8 wk,and AML-12 cells were treated with 200μM palmitate acid for 24 h.For AITC treatment,mice were administered AITC(100 mg/kg/d)orally and AML-12 cells were treated with AITC(20μmol/L).RESULTS AITC significantly ameliorated HFD-induced weight gain,hepatic lipid accumulation and inflammation in vivo.Furthermore,serum alanine aminotransferase and aspartate aminotransferase levels were markedly reduced in AITC-treated mice.Mechanistically,AITC significantly downregulated the protein levels of sterol regulatory elementbinding protein 1(SREBP1)and its lipogenesis target genes and upregulated the levels of proteins involved in fatty acidβ-oxidation,as well as the upstream mediators Sirtuin 1(Sirt1)and AMPactivated protein kinaseα(AMPKα),in the livers of HFD-fed mice.AITC also attenuated the nuclear factor kappa B(NF-κB)signaling pathway.Consistently,AITC relieved palmitate acid-induced lipid accumulation and inflammation in AML-12 cells in vitro through the Sirt1/AMPK and NF-κB signaling pathways.Importantly,further studies showed that the curative effect of AITC on lipid accumulation was abolished by siRNA-mediated knockdown of either Sirt1 or AMPKαin AML-12 cells.CONCLUSION AITC significantly ameliorates hepatic steatosis and inflammation by activating the Sirt1/AMPK pathway and inhibiting the NF-κB pathway.Therefore,AITC is a potential therapeutic agent for NAFLD.展开更多
BACKGROUND It is well known that nonalcoholic fatty liver disease(NAFLD)is associated with insulin resistance(IR).LB100,a serine/threonine protein phosphatase 2A(PP2A)inhibitor,is closely related to IR.However,there i...BACKGROUND It is well known that nonalcoholic fatty liver disease(NAFLD)is associated with insulin resistance(IR).LB100,a serine/threonine protein phosphatase 2A(PP2A)inhibitor,is closely related to IR.However,there is little data regarding its direct influence on NAFLD.AIM To elucidate the effect and underlying mechanism of LB100 in NAFLD.METHODS After 10 wk of high fat diet(HFD)feeding,male C57BL/6 mice were injected intraperitoneally with vehicle or LB100 for an additional 6 wk(three times a week).The L02 cell line was treated with LB100 and free fatty acids(FFAs)for 24 h.Hematoxylin and eosin and oil red O staining were performed for histological examination.Western blot analysis was used to detect the protein expression of Sirtuin 1(Sirt1),total and phosphorylated AMP-activated protein kinaseα(AMPKα),and the proteins involved in lipogenesis and fatty acid oxidation.The mRNA levels were determined by qPCR.Pharmacological inhibition of AMPK was performed to further examine the exact mechanism of LB100 in NAFLD.RESULTS LB100 significantly ameliorated HFD-induced obesity,hepatic lipid accumulation and hepatic injury in mice.In addition,LB100 significantly downregulated the protein levels of acetyl-CoA carboxylase,sterol regulatory element-binding protein 1 and its lipogenesis target genes,including stearoyl-CoA desaturase-1 and fatty acid synthase,and upregulated the levels of proteins involved in fatty acidβ-oxidation,such as peroxisome proliferator-activated receptorα(PPARα),peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α),carnitine palmitoyltransferase 1α,acyl-CoA oxidase 1 and uncoupling protein 2,as well as the upstream mediators Sirt1 and AMPKαin the livers of HFD-fed mice.In vitro,LB100 alleviated FFA-induced lipid accumulation in L02 cells through the AMPK/Sirt1 signaling pathway.Further studies showed that the curative effect of LB100 on lipid accumulation was abolished by inhibiting AMPKαin L02 cells.CONCLUSION PP2A inhibition by LB100 significantly ameliorates hepatic steatosis by regulating hepatic lipogenesis and fatty acid oxidation via the AMPK/Sirt1 pathway.LB100 may be a potential therapeutic agent for NAFLD.展开更多
基金Supported by Natural Science Foundation of China,No.81700504 and No.81700511Science Foundation of Health Bureau of Zhejiang Province,No.2017183691+1 种基金Natural Science Foundation of Zhejiang Province,No.LY17H030006 and No.LQ15H030002Zhejiang Medical Science and Technology Project,No.2017193668
文摘BACKGROUND Allyl isothiocyanate(AITC),a classic anti-inflammatory and antitumorigenic agent,was recently identified as a potential treatment for obesity and insulin resistance.However,little is known about its direct impact on the liver.AIM To investigate the effect and underlying mechanism of AITC in nonalcoholic fatty liver disease(commonly referred to as NAFLD).METHODS To establish a mouse and cellular model of NAFLD,C57BL/6 mice were fed a high fat diet(HFD)for 8 wk,and AML-12 cells were treated with 200μM palmitate acid for 24 h.For AITC treatment,mice were administered AITC(100 mg/kg/d)orally and AML-12 cells were treated with AITC(20μmol/L).RESULTS AITC significantly ameliorated HFD-induced weight gain,hepatic lipid accumulation and inflammation in vivo.Furthermore,serum alanine aminotransferase and aspartate aminotransferase levels were markedly reduced in AITC-treated mice.Mechanistically,AITC significantly downregulated the protein levels of sterol regulatory elementbinding protein 1(SREBP1)and its lipogenesis target genes and upregulated the levels of proteins involved in fatty acidβ-oxidation,as well as the upstream mediators Sirtuin 1(Sirt1)and AMPactivated protein kinaseα(AMPKα),in the livers of HFD-fed mice.AITC also attenuated the nuclear factor kappa B(NF-κB)signaling pathway.Consistently,AITC relieved palmitate acid-induced lipid accumulation and inflammation in AML-12 cells in vitro through the Sirt1/AMPK and NF-κB signaling pathways.Importantly,further studies showed that the curative effect of AITC on lipid accumulation was abolished by siRNA-mediated knockdown of either Sirt1 or AMPKαin AML-12 cells.CONCLUSION AITC significantly ameliorates hepatic steatosis and inflammation by activating the Sirt1/AMPK pathway and inhibiting the NF-κB pathway.Therefore,AITC is a potential therapeutic agent for NAFLD.
文摘BACKGROUND It is well known that nonalcoholic fatty liver disease(NAFLD)is associated with insulin resistance(IR).LB100,a serine/threonine protein phosphatase 2A(PP2A)inhibitor,is closely related to IR.However,there is little data regarding its direct influence on NAFLD.AIM To elucidate the effect and underlying mechanism of LB100 in NAFLD.METHODS After 10 wk of high fat diet(HFD)feeding,male C57BL/6 mice were injected intraperitoneally with vehicle or LB100 for an additional 6 wk(three times a week).The L02 cell line was treated with LB100 and free fatty acids(FFAs)for 24 h.Hematoxylin and eosin and oil red O staining were performed for histological examination.Western blot analysis was used to detect the protein expression of Sirtuin 1(Sirt1),total and phosphorylated AMP-activated protein kinaseα(AMPKα),and the proteins involved in lipogenesis and fatty acid oxidation.The mRNA levels were determined by qPCR.Pharmacological inhibition of AMPK was performed to further examine the exact mechanism of LB100 in NAFLD.RESULTS LB100 significantly ameliorated HFD-induced obesity,hepatic lipid accumulation and hepatic injury in mice.In addition,LB100 significantly downregulated the protein levels of acetyl-CoA carboxylase,sterol regulatory element-binding protein 1 and its lipogenesis target genes,including stearoyl-CoA desaturase-1 and fatty acid synthase,and upregulated the levels of proteins involved in fatty acidβ-oxidation,such as peroxisome proliferator-activated receptorα(PPARα),peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α),carnitine palmitoyltransferase 1α,acyl-CoA oxidase 1 and uncoupling protein 2,as well as the upstream mediators Sirt1 and AMPKαin the livers of HFD-fed mice.In vitro,LB100 alleviated FFA-induced lipid accumulation in L02 cells through the AMPK/Sirt1 signaling pathway.Further studies showed that the curative effect of LB100 on lipid accumulation was abolished by inhibiting AMPKαin L02 cells.CONCLUSION PP2A inhibition by LB100 significantly ameliorates hepatic steatosis by regulating hepatic lipogenesis and fatty acid oxidation via the AMPK/Sirt1 pathway.LB100 may be a potential therapeutic agent for NAFLD.
