This study aimed to verify the effects of berberine(BBR)on the fat metabolism proteins involved in the sirtuin 3(SIRT3)/adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)/acetyl-CoA carboxylase(ACC)pat...This study aimed to verify the effects of berberine(BBR)on the fat metabolism proteins involved in the sirtuin 3(SIRT3)/adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)/acetyl-CoA carboxylase(ACC)pathway in the liver tissues of rats with high-fat diet(HFD)-induced non-alcoholic fatty liver disease(NAFLD).Forty-eight rats were randomly divided into the normal control(NC)group,HFD group or BBR group,with 16 rats in each group.After 8 and 16 weeks of treatment,serum and liver samples were collected.Subsequently,body parameters,biochemical parameters and liver pathology were examined.The expression levels of proteins involved in the SIRT3/AMPK/ACC pathway in the liver were detected by Western blotting.After 8 and 16 weeks of a HFD,the successful establishment of rat models with different degrees of NAFLD was confirmed by hematoxylin and eosin(H&E)and Oil Red O staining.NAFLD rat models exhibited obesity and hyperlipidemia,and the protein expression levels of SIRT3,p-AMPK.p-ACC,and CPT-1A in the liver were significantly decreased compared to those in the NC group.The concurrent administration of BBR with the HFD effectively improved serum and liver lipid profiles and ameliorated liver injury.Furthermore,the protein expression levels of SIRT3,p-AMPK,p-ACC,and CPT-1 A in the liver were significantly increased in the BBR group as compared with those in the HFD group.In conclusion,our data suggest that the mechanism by which BBR ameliorates HFD-induced hepatic steatosis may be related to the activation of the SIRT3/AMPK/ACC pathway in the liver.展开更多
The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide has increased at an alarming rate, which will likely result in enormous medical and economic burden. NAFLD presents as a spectrum of liver diseases ...The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide has increased at an alarming rate, which will likely result in enormous medical and economic burden. NAFLD presents as a spectrum of liver diseases ranging from simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even to hepatocellular carcinoma (HCC). A comprehensive understanding of the mechanism(s) of NAFLD-to-NASH transition remains elusive with various genetic and environmental susceptibility factors possibly involved. An understanding of the mechanism may provide novel strategies in the prevention and treatment to NASH. Abnormal regulation of bile acid homeostasis emerges as an important mechanism to liver injury. The bile acid homeostasis is critically regulated by the farnesoid X receptor (FXR) that is activated by bile acids. FXR has been known to exert tissue-specific effects in regulating bile acid synthesis and transport. Current investigations demonstrate FXR also plays a principle role in regulating lipid metabolism and suppressing inflammation in the liver. Therefore, the future determination of the molecular mechanism by which FXR protects the liver from developing NAFLD may shed light to the prevention and treatment of NAFLD. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.展开更多
The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeos...The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size,and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor(FXR)and the G-protein-coupled bile acid receptor(TGR5).展开更多
Nonalcoholic fatty liver disease(NAFLD)has become one of the most prominent causes of chronic liver diseases and malignancies.However,few therapy has been approved.Radix Bupleuri(RB)is the most frequently used herbal ...Nonalcoholic fatty liver disease(NAFLD)has become one of the most prominent causes of chronic liver diseases and malignancies.However,few therapy has been approved.Radix Bupleuri(RB)is the most frequently used herbal medicine for the treatment of liver diseases.In the current study,we aim to systemically evaluate the therapeutic effects of saikosaponin A(SSa)and saikosaponin D(SSd),the major bioactive monomers in RB,against NAFLD and to investigate the underlying mechanisms.Our results demonstrated that both SSa and SSd improved diet-induced NAFLD.Integrative lipidomic and transcriptomic analysis revealed that SSa and SSd modulated glycerolipid metabolism by regulating related genes,like Lipe and Lipg.SSd profoundly suppressed the fatty acid biosynthesis by downregulating Fasn and Acaca expression and promoted fatty acid degradation by inducing Acox1 and Cpt1 a expression.Bioinformatic analysis further predicted the implication of master transcription factors,including peroxisome proliferator-activated receptor alpha(PPARα),in the protective effects of SSa and SSd.These results were further confirmed in vitro in mouse primary hepatocytes.In summary,our study uncoded the complicated mechanisms underlying the promising anti-steatosis activities of saikosaponins(SSs),and provided critical evidence inspiring the discovery of innovative therapies based on SSa and SSd for the treatment of NAFLD and related complications.展开更多
Autophagy is a mechanism involved in cellular homeostasis under basal and stressed conditions delivering cytoplasmic content to the lysosomes for degradation to macronutrients.The potential role of autophagy in diseas...Autophagy is a mechanism involved in cellular homeostasis under basal and stressed conditions delivering cytoplasmic content to the lysosomes for degradation to macronutrients.The potential role of autophagy in disease is increasingly recognised and investigated in the last decade.Nowadays it is commonly accepted that autophagy plays a role in the hepatic lipid metabolism.Hence,dysfunction of autophagy may be an underlying cause of non-alcoholic fatty liver disease.However,controversy of the exact role of autophagy in the lipid metabolism exists:some publications report a lipolytic function of autophagy,whereas others claim a lipogenic function.This review aims to give an update of the present knowledge on autophagy in the hepatic lipid metabolism,hepatic insulin resistance,steatohepatitis and hepatic fibrogenesis.展开更多
The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis.Metabolism of xenobiotics,such as environmental chemicals and drugs by the liver protects us from toxic effects o...The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis.Metabolism of xenobiotics,such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics,whereas metabolism of cholesterol,bile acids(BAs),lipids,and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism.As a wellestablished master regulator of liver development and function,hepatocyte nuclear factor 4 alpha(HNF4α)plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics,metabolic wastes,and nutrients.The expression and activity of HNF4α is regulated by diverse hormonal and signaling pathways such as growth hormone,glucocorticoids,thyroid hormone,insulin,transforming growth factor-β,estrogen,and cytokines.HNF4α appears to play a central role in orchestrating the transduction of extracellular hormonal signaling and intracellular stress/nutritional signaling onto transcriptional changes in the liver.There have been a few reviews on the regulation of drug metabolism,lipid metabolism,cell proliferation,and inflammation by HNF4α.However,the knowledge on how the expression and transcriptional activity of HNF4α is modulated remains scattered.Herein I provide comprehensive review on the regulation of expression and transcriptional activity of HNF4α,and how HNF4α crosstalks with diverse extracellular and intracellular signaling pathways to regulate genes essential in liver pathophysiology.展开更多
AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis.METHODS: Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitat...AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis.METHODS: Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations (25 to 100 μmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays.RESULTS: Lipid-loading resulted in intracellular triglyceride (TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species (ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B (NF-κB). Incubation of steatotic cells with silybin 50 μmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1 (CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-κB activation.CONCLUSION: We demonstrated the direct anti-steatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies.展开更多
基金grants from the National Natural Science Foundation of China(No.81573844 and No.81774165)Medical Research Fund of Guangdong Province(No.A2017363).
文摘This study aimed to verify the effects of berberine(BBR)on the fat metabolism proteins involved in the sirtuin 3(SIRT3)/adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)/acetyl-CoA carboxylase(ACC)pathway in the liver tissues of rats with high-fat diet(HFD)-induced non-alcoholic fatty liver disease(NAFLD).Forty-eight rats were randomly divided into the normal control(NC)group,HFD group or BBR group,with 16 rats in each group.After 8 and 16 weeks of treatment,serum and liver samples were collected.Subsequently,body parameters,biochemical parameters and liver pathology were examined.The expression levels of proteins involved in the SIRT3/AMPK/ACC pathway in the liver were detected by Western blotting.After 8 and 16 weeks of a HFD,the successful establishment of rat models with different degrees of NAFLD was confirmed by hematoxylin and eosin(H&E)and Oil Red O staining.NAFLD rat models exhibited obesity and hyperlipidemia,and the protein expression levels of SIRT3,p-AMPK.p-ACC,and CPT-1A in the liver were significantly decreased compared to those in the NC group.The concurrent administration of BBR with the HFD effectively improved serum and liver lipid profiles and ameliorated liver injury.Furthermore,the protein expression levels of SIRT3,p-AMPK,p-ACC,and CPT-1 A in the liver were significantly increased in the BBR group as compared with those in the HFD group.In conclusion,our data suggest that the mechanism by which BBR ameliorates HFD-induced hepatic steatosis may be related to the activation of the SIRT3/AMPK/ACC pathway in the liver.
基金supported by the U.S. National Institutes of Health (NIH,Nos.DK081343 and R01GM104037)fund from the University of Kansas Medical Center and Rutgers University,USA
文摘The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide has increased at an alarming rate, which will likely result in enormous medical and economic burden. NAFLD presents as a spectrum of liver diseases ranging from simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even to hepatocellular carcinoma (HCC). A comprehensive understanding of the mechanism(s) of NAFLD-to-NASH transition remains elusive with various genetic and environmental susceptibility factors possibly involved. An understanding of the mechanism may provide novel strategies in the prevention and treatment to NASH. Abnormal regulation of bile acid homeostasis emerges as an important mechanism to liver injury. The bile acid homeostasis is critically regulated by the farnesoid X receptor (FXR) that is activated by bile acids. FXR has been known to exert tissue-specific effects in regulating bile acid synthesis and transport. Current investigations demonstrate FXR also plays a principle role in regulating lipid metabolism and suppressing inflammation in the liver. Therefore, the future determination of the molecular mechanism by which FXR protects the liver from developing NAFLD may shed light to the prevention and treatment of NAFLD. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
基金supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH,No.R01DK047987)supported by a Research Supplement to Promote Diversity in Health Related Research from the NIH
文摘The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size,and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor(FXR)and the G-protein-coupled bile acid receptor(TGR5).
基金supported by grants from the National Natural Science Foundation of China(Nos.81773997 and 81073148 to Rong SunNo.82004029 to Runping Liu+3 种基金No.82004045 to Xiaojiaoyang Li)Beijing University of Chinese Medicine(No.2020-JYB-ZDGG-038 to Runping Liu,China)supported by grants from Beijing Nova Program of Science&Technology(Nos.Z201100006820025 and Z191100001119088,China)supported by research fund‘Traditional Chinese medicine pharmacology and toxicology expert(No.ts201511107)’from the Taishan Scholar Project of Shandong Province(China)。
文摘Nonalcoholic fatty liver disease(NAFLD)has become one of the most prominent causes of chronic liver diseases and malignancies.However,few therapy has been approved.Radix Bupleuri(RB)is the most frequently used herbal medicine for the treatment of liver diseases.In the current study,we aim to systemically evaluate the therapeutic effects of saikosaponin A(SSa)and saikosaponin D(SSd),the major bioactive monomers in RB,against NAFLD and to investigate the underlying mechanisms.Our results demonstrated that both SSa and SSd improved diet-induced NAFLD.Integrative lipidomic and transcriptomic analysis revealed that SSa and SSd modulated glycerolipid metabolism by regulating related genes,like Lipe and Lipg.SSd profoundly suppressed the fatty acid biosynthesis by downregulating Fasn and Acaca expression and promoted fatty acid degradation by inducing Acox1 and Cpt1 a expression.Bioinformatic analysis further predicted the implication of master transcription factors,including peroxisome proliferator-activated receptor alpha(PPARα),in the protective effects of SSa and SSd.These results were further confirmed in vitro in mouse primary hepatocytes.In summary,our study uncoded the complicated mechanisms underlying the promising anti-steatosis activities of saikosaponins(SSs),and provided critical evidence inspiring the discovery of innovative therapies based on SSa and SSd for the treatment of NAFLD and related complications.
基金Supported by Fund for Scientific Research(FWO)-Flanders(11J9513N,G007412N,G044312N,1802514N),to Kwanten WJ,Martinet W and Francque SM
文摘Autophagy is a mechanism involved in cellular homeostasis under basal and stressed conditions delivering cytoplasmic content to the lysosomes for degradation to macronutrients.The potential role of autophagy in disease is increasingly recognised and investigated in the last decade.Nowadays it is commonly accepted that autophagy plays a role in the hepatic lipid metabolism.Hence,dysfunction of autophagy may be an underlying cause of non-alcoholic fatty liver disease.However,controversy of the exact role of autophagy in the lipid metabolism exists:some publications report a lipolytic function of autophagy,whereas others claim a lipogenic function.This review aims to give an update of the present knowledge on autophagy in the hepatic lipid metabolism,hepatic insulin resistance,steatohepatitis and hepatic fibrogenesis.
基金partly supported by U.S. National Institute of Health (NIH) Grant ES019487
文摘The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis.Metabolism of xenobiotics,such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics,whereas metabolism of cholesterol,bile acids(BAs),lipids,and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism.As a wellestablished master regulator of liver development and function,hepatocyte nuclear factor 4 alpha(HNF4α)plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics,metabolic wastes,and nutrients.The expression and activity of HNF4α is regulated by diverse hormonal and signaling pathways such as growth hormone,glucocorticoids,thyroid hormone,insulin,transforming growth factor-β,estrogen,and cytokines.HNF4α appears to play a central role in orchestrating the transduction of extracellular hormonal signaling and intracellular stress/nutritional signaling onto transcriptional changes in the liver.There have been a few reviews on the regulation of drug metabolism,lipid metabolism,cell proliferation,and inflammation by HNF4α.However,the knowledge on how the expression and transcriptional activity of HNF4α is modulated remains scattered.Herein I provide comprehensive review on the regulation of expression and transcriptional activity of HNF4α,and how HNF4α crosstalks with diverse extracellular and intracellular signaling pathways to regulate genes essential in liver pathophysiology.
基金Supported by MIUR-COFIN(Prot.20089SRS2X_002)Compagnia San Paolo Torino+1 种基金University of Genovaand Fondazione CARIGE
文摘AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis.METHODS: Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations (25 to 100 μmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays.RESULTS: Lipid-loading resulted in intracellular triglyceride (TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species (ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B (NF-κB). Incubation of steatotic cells with silybin 50 μmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1 (CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-κB activation.CONCLUSION: We demonstrated the direct anti-steatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies.
