Bile acids and insulin resistance: implications for treating nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease is characterized by an accumulation of excess triglycerides in hepatocytes, and insulin resistance is now considered the fundamental operative mechanism throughout the prevalence and progression of the disease. Besides their role in dietary lipid absorption and cholesterol homeostasis, evidence has accumulated that bile acids are also signaling molecules that play two important roles in glucose and lipid metabolism: in the nuclear hormone receptors as farnesoid X receptors (FXR), as well as ligands for G-protein-coupled receptors TGR5. The activated FXR-SHP pathway regulates the enterohepatic recycling and biosynthesis of bile acids and underlies the down-regulation of hepatic fatty acid and triglyceride biosynthesis and very low density lipoprotein production mediated by sterol-regulatory element-binding protein-1c. The bile acid-TGR5-cAMP-D2 signaling pathway in human skeletal muscle in the fasting-feeding cycle increases energy expenditure and prevents obesity. Therefore, a molecular basis has been provided for a link between bile acids, lipid metabolism and glucose homeostasis, which can open novel pharmacological approaches against insulin resistance and nonalcoholic fatty liver disease.
Wei
Jue
J
Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China.
Qiu
De Kai
DK
Ma
Xiong
X
D000818:Animals; D001647:Bile Acids and Salts / Q000502:physiology* / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000502:physiology; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D005947:Glucose; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human