Nonalcoholic fatty liver disease(NAFLD),a leading chronic disease worldwide,affects approximately a quarter of the global population.Nonalcoholic steatohepatitis(NASH)is an advanced form of NAFLD and is more likely to...Nonalcoholic fatty liver disease(NAFLD),a leading chronic disease worldwide,affects approximately a quarter of the global population.Nonalcoholic steatohepatitis(NASH)is an advanced form of NAFLD and is more likely to progress to liver fibrosis than simple steatosis.NASH is also identified as the most rapidly growing cause of hepatocellular carcinoma.Although in the past decade,several phase II/III clinical trials have shown promising results in the use of novel drugs targeting lipid synthase,farnesoid X receptor signaling,peroxisome proliferatoractivated receptor signaling,hepatocellular injury,and inflammatory signaling,proven pharmaceutical agents to treat NASH are still lacking.Thus,continuous exploration of the mechanism underlying the pathogenesis of NAFLD and the identification of novel therapeutic targets remain urgent tasks in the field.In the current review,we summarize studies reported in recent years that not only provide new insights into the mechanisms of NAFLD development but also explore the possibility of treating NAFLD by targeting newly identified signaling pathways.We also discuss evidence focusing on the intrahepatic targets involved in the pathogenesis of NAFLD as well as extrahepatic targets affecting liver metabolism and function.展开更多
Among the four prostaglandin E2 receptors,EP3 receptor is the one most abundantly expressed in white adipose tissue(WAT).The mouse EP3 gene gives rise to three isoforms,namely EP3α,EP3β,and EP3γ,which differ only a...Among the four prostaglandin E2 receptors,EP3 receptor is the one most abundantly expressed in white adipose tissue(WAT).The mouse EP3 gene gives rise to three isoforms,namely EP3α,EP3β,and EP3γ,which differ only at their C-terminal tails.To date,functions of EP3 receptor and its isoforms in WAT remain incompletely characterized.In this study,we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice.Genetic ablation of three EP3 receptor isoforms(EP3^(−/−)mice)or EP3αand EP3γisoforms with EP3βintact(EP3βmice)led to an obese phenotype with increased food intake,decreased motor activity,reduced insulin sensitivity,and elevated serum triglycerides.Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγpathway,increased adipogenesis may contribute to obesity in EP3^(−/−)and EP3βmice.Moreover,both EP3^(−/−)and EP3βmice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway.Taken together,our findings suggest that EP3 receptor and itsαandγisoforms are involved in both adipogenesis and lipolysis and influence food intake,serum lipid levels,and insulin sensitivity.展开更多
AIM:To survey glutathione(GSH) S-transferase(GST) isoforms in mitochondria and to reveal the isoforms' biological significance in diabetic mice.METHODS:The presence of GSTs in mouse liver mitochondria was systemat...AIM:To survey glutathione(GSH) S-transferase(GST) isoforms in mitochondria and to reveal the isoforms' biological significance in diabetic mice.METHODS:The presence of GSTs in mouse liver mitochondria was systematically screened by two proteomic approaches,namely,GSH affinity chromatography/two dimensional electrophoresis(2DE/MALDI TOF/TOF MS) and SDS-PAGE/LC ESI MS/MS.The proteomic results were further confirmed by Western blotting using monoclonal antibodies against GSTs.To evaluate the liver mitochondrial GSTs quantitatively,calibration curves were generated by the loading amounts of individual recombinant GST protein vs the relative intensities elicited from the Western blotting.An extensive comparison of the liver mitochondrial GSTs was conducted between normal and db/db diabetic mice.Student's t test was adopted for the estimation of regression and significant difference.RESULTS:Using GSH affinity/2DE/MALDI TOF/TOF MS,three GSTs,namely,alpha3,mu1 and pi1,were identified;whereas five GSTs,alpha3,mu1,pi1,kappa1 and zeta1,were detected in mouse liver mitochondria using SDS-PAGE/LC ESI MS/MS,of these GSTs,GST kappa1 was reported as a specific mitochondrial GST.The R 2 values of regression ranged between values of about 0.86 and 0.98,which were acceptable for the quantification.Based on the measurement of the GST abundances in liver mitochondria of normal and diabetic mice,the four GSTs,alpha3,kappa1,mu1 and zeta1,were found to be almost comparable between the two sets of animals,whereas,lower GST pi1 was detected in the diabetic mice compared with normal ones,the signal of Western blotting in control and db/db diabetic mice liver mitochondria is 134.61 ± 53.84 vs 99.74 ± 46.2,with P < 0.05.CONCLUSION:Our results indicate that GSTs exist widely in mitochondria and its abundances of mitochondrial GSTs might be tissue-dependent and disease-related.展开更多
基金National Natural Science Foundation of China,No.82170635,No.81822006,and No.81970606Natural Science Foundation of Tianjin,No.20JCYBJC01120.
文摘Nonalcoholic fatty liver disease(NAFLD),a leading chronic disease worldwide,affects approximately a quarter of the global population.Nonalcoholic steatohepatitis(NASH)is an advanced form of NAFLD and is more likely to progress to liver fibrosis than simple steatosis.NASH is also identified as the most rapidly growing cause of hepatocellular carcinoma.Although in the past decade,several phase II/III clinical trials have shown promising results in the use of novel drugs targeting lipid synthase,farnesoid X receptor signaling,peroxisome proliferatoractivated receptor signaling,hepatocellular injury,and inflammatory signaling,proven pharmaceutical agents to treat NASH are still lacking.Thus,continuous exploration of the mechanism underlying the pathogenesis of NAFLD and the identification of novel therapeutic targets remain urgent tasks in the field.In the current review,we summarize studies reported in recent years that not only provide new insights into the mechanisms of NAFLD development but also explore the possibility of treating NAFLD by targeting newly identified signaling pathways.We also discuss evidence focusing on the intrahepatic targets involved in the pathogenesis of NAFLD as well as extrahepatic targets affecting liver metabolism and function.
基金supported by the National Basic Research Program of China(973 Program)(2012CB517504 to Y.-F.G.)the National Natural Science Foundation of China(81390351,81270275,81200511,and 81030003 to Y.-F.G.)+1 种基金National Institutes of Health grants(DK46205 to R.M.B.)the Swedish Research Council(to J.-A.G.),and Shenzhen Peacock Plan&JCYJ 20140418095735626.
文摘Among the four prostaglandin E2 receptors,EP3 receptor is the one most abundantly expressed in white adipose tissue(WAT).The mouse EP3 gene gives rise to three isoforms,namely EP3α,EP3β,and EP3γ,which differ only at their C-terminal tails.To date,functions of EP3 receptor and its isoforms in WAT remain incompletely characterized.In this study,we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice.Genetic ablation of three EP3 receptor isoforms(EP3^(−/−)mice)or EP3αand EP3γisoforms with EP3βintact(EP3βmice)led to an obese phenotype with increased food intake,decreased motor activity,reduced insulin sensitivity,and elevated serum triglycerides.Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγpathway,increased adipogenesis may contribute to obesity in EP3^(−/−)and EP3βmice.Moreover,both EP3^(−/−)and EP3βmice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway.Taken together,our findings suggest that EP3 receptor and itsαandγisoforms are involved in both adipogenesis and lipolysis and influence food intake,serum lipid levels,and insulin sensitivity.
基金Supported by The National Basic Research Program of China,No. 2010CB912703the Development Program of China,No.2006AA02A308the Nature Science Foundation of China,No. 30900508
文摘AIM:To survey glutathione(GSH) S-transferase(GST) isoforms in mitochondria and to reveal the isoforms' biological significance in diabetic mice.METHODS:The presence of GSTs in mouse liver mitochondria was systematically screened by two proteomic approaches,namely,GSH affinity chromatography/two dimensional electrophoresis(2DE/MALDI TOF/TOF MS) and SDS-PAGE/LC ESI MS/MS.The proteomic results were further confirmed by Western blotting using monoclonal antibodies against GSTs.To evaluate the liver mitochondrial GSTs quantitatively,calibration curves were generated by the loading amounts of individual recombinant GST protein vs the relative intensities elicited from the Western blotting.An extensive comparison of the liver mitochondrial GSTs was conducted between normal and db/db diabetic mice.Student's t test was adopted for the estimation of regression and significant difference.RESULTS:Using GSH affinity/2DE/MALDI TOF/TOF MS,three GSTs,namely,alpha3,mu1 and pi1,were identified;whereas five GSTs,alpha3,mu1,pi1,kappa1 and zeta1,were detected in mouse liver mitochondria using SDS-PAGE/LC ESI MS/MS,of these GSTs,GST kappa1 was reported as a specific mitochondrial GST.The R 2 values of regression ranged between values of about 0.86 and 0.98,which were acceptable for the quantification.Based on the measurement of the GST abundances in liver mitochondria of normal and diabetic mice,the four GSTs,alpha3,kappa1,mu1 and zeta1,were found to be almost comparable between the two sets of animals,whereas,lower GST pi1 was detected in the diabetic mice compared with normal ones,the signal of Western blotting in control and db/db diabetic mice liver mitochondria is 134.61 ± 53.84 vs 99.74 ± 46.2,with P < 0.05.CONCLUSION:Our results indicate that GSTs exist widely in mitochondria and its abundances of mitochondrial GSTs might be tissue-dependent and disease-related.
