The prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has rapidly increased world-wide to 30％,with increasing of type 2 diabetes(T2D)and obesity in last two decades.The spectrum of MASLD covers from simple hepatic steatosis to the progressive metabolic dysfunction-associated steatohepatitis(MASH)with or without fibrosis,cirrhosis and hepatocellular carcinoma.The MASLD symptoms include dyslipidemia,hyperglycemia,insulin resistance and obesity,the liver manifestations of metabolic syndrome.Treatment option for MASH fibrosis is limited.Since the discovery of bile acids as the endogenous ligands of farnesoid X receptor(FXR)in early 1990,bile acid and FXR based-drug therapies have been developed and tested in clinical trials for cholestatic liver diseases and MASH fibrosis.However,many of these drugs have unwanted side-effects and moderate efficacy in improving fibrosis.The US Food and Drug Administration has not approved any of bile acid-and FXR-based drugs for MASH fibrosis.Drug therapies alternative to bile acid derivatives for MASH have been in clinical trials.Recently,resmetirom,a liver-specific-and thyroid hormone receptor beta-selective agonist has been approved for MASH fibrosis.Glucagon-like peptide-1 receptor agonists also are in clinical trials for MASH.This review covers recent development of novel drug therapies for MASH fibrosis,T2D and obesity.

Cholesterol 7 alpha-hydroxylase(CYP7A1,EC1.14)is the first and rate-limiting enzyme in the classic bile acid synthesis pathway.Much progress has been made in understanding the transcriptional regulation of CYP7A1 gene expression and the underlying molecular mechanisms of bile acid feedback regulation of CYP7A1 and bile acid synthesis in the last three decades.Discovery of bile acid-activated receptors and their roles in the regulation of lipid,glucose and energy metabolism have been translated to the development of bile acid-based drug therapies for the treatment of liver-related metabolic diseases such as alcoholic and non-alcoholic fatty liver diseases,liver cirrhosis,diabetes,obesity and hepatocellular carcinoma.This review will provide an update on the advances in our understanding of the molecular biology and mechanistic insights of the regulation of CYP7A1 in bile acid synthesis in the last 40 years.

Bile acids play a critical role in the regulation of glucose,lipid,and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor(FXR)and membrane G protein-coupled bile acid receptor-1(Gpbar-1,aka TGR5).Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes,obesity,and non-alcoholic fatty liver disease(NAFLD).Bile acids have both pro-and anti-inflammatory actions through FXR and TGR5 in the intestine and liver.In the intestine,bile acids activate FXR and TGR5 to stimulate fibroblast growth factor 15 and glucagon-like peptide-1 secretion.FXR and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases,such as diabetes and NAFLD.