Circadian rhythms in liver metabolism and disease

Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia.Here, these associations are reviewed with respect to liver metabolism and disease.

Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic Iiver disease

Bile acids are synthesized from cholesterol only in hepatocytes.Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine.Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor(FXR)and cell surface G protein-coupled receptor TGR5.FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis.In addition,bile acid-activated cellular signaling pathways regulate metabolic homeostasis,immunity,and cell proliferation in various metabolically active organs.In the small and large intestine,gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects.In turn,bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity.Currently,bile acid-based therapies including systemic and intestine-restricted FXR agonists,TGR5 agonists,fibroblast growth factor 19 analogue,intestine FXR antagonists,and intestine apical sodium-bile acid transporter(ASBT)inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis(NASH).These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest.More recently,human and experimental alcoholic liver disease(ALD)has been associated with disrupted bile acid homeostasis.In additional,new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.

Bile acid receptors and signaling crosstalk in the liver, gut and brain

Bile acids are physiological detergents derived from cholesterol that aid in digestion and nutrient ab-sorption,and they play roles in glucose,lipid,and energy metabolism and in gut microbiome and metabolic homeostasis.Bile acids mediate crosstalk between the liver and gut through bactericidal modulation of the gut microbiome,while gut microbes influence the composition of the circulating bile acid pool.Recent research indicates bile acids may also be important mediators of neurological disease by acting as peripheral signaling molecules that activate bile acid receptors in the blood-brain barrier and in the brain itself.This review highlights the role of bile acids in maintaining liver and gut microbe homeostasis,as well as their function as mediators of cellular signaling in the liver-gut-brain axis.

Bile acid metabolism and signaling in liver disease and therapy

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.

Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis

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 acid metabolism and bile acid receptor signaling in metabolic diseases and therapy

Bile acids are nutrient sensors and metabolic regulators that control nutrient intake and gut bacteria growth to regulate glucose,lipid,and energy homeostasis.Dysregulation of bile acid meta-bolism causes dysbiosis leading to obesity,diabetes,and liver-related diseases.Bile acids and their derivatives have emerged as therapeutic drugs for treating liver metabolic and cholestatic dis-eases,type 2 diabetes,and non-alcoholic steatohepatitis(NASH).This special issue covers five emerging topics in bile acid research in metabolic diseases:(i)bile acid synthesis and metabolism in liver metabolic diseases;(ii)bile acid-activated receptors and signaling in liver metabolism and diseases;(iii)gut microbiome in liver path-ophysiology and cholestasis;(iv)bile acid metabolism in metabolic gastric surgery;and(v)cholestasis-associated renal injury,disease,and therapy.

Altered serotonin metabolism in Takeda G protein-coupled receptor 5 knockout mice protects against diet-induced hepatic fibrosis

Background and aims:Diet-induced obesity and metabolic syndrome can trigger the progression of fatty liver disease to non-alcoholic steatohepatitis and fibrosis,which is a major public health concern.Bile acids regulate metabolic homeostasis and inflammation in the liver and gut via the activation of nuclear farnesoid X receptor(Fxr)and the membrane receptor Takeda G protein-coupled receptor 5(Tgr5).Tgr5 is highly expressed in the gut and skeletal muscle,and in cholangiocytes and Kupffer cells of the liver.Tgr5 is implicated in the mediation of liver and gut inflammation,as well as the maintenance of energy homeostasis.Here,we used a high fat,high fructose,and high sucrose(HFS)diet to determine how bile acid signaling through Tgr5 may regulate metabolism during the progression from fatty liver to non-alcoholic steatohepatitis and fibrosis.Materials and methods:Female C57BL/6J control wild type(WT)and Tgr5 knockout(Tgr5^(-/-))mice were fed HFS(high fat(40%kcal),high fructose,and 20%sucrose water)diet for 20 weeks.Metabolic phe-notypes were characterized through examination of bile acid synthesis pathways,lipid and cholesterol metabolism pathways,and fibrosis and inflammation pathways.Results:Tgr5^(-/-)mice were more glucose intolerant when fed HFS diet,despite gaining the same amount of weight as WT mice.Tgr5^(-/-)mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice,and gene expression of lipogenic genes was significantly upregulated.Hepatic cholesterol 7alpha-hydroxylase(Cyp7a1)gene expression was consistently elevated in Tgr5^(-/-)mice,while oxysterol 7alpha-hydroxylase(Cyp7b1),sterol 27-hydroxylase(Cyp27a1),Fxr,and small heterodimer partner(Shp)were downregulated by HFS diet.Surprisingly,hepatic inflammation and fibrosis were also significantly reduced in Tgr5^(-/-)mice fed HFS diet,which may be due to altered se-rotonin signaling in the liver.Conclusions:Tgr5^(-/-)mice may be protected from high fat,high sugar-induced hepatic inflammation and injury due to altered serotonin metabolism.

Pathogenesis of fatty liver diseases and hepatocellular carcinoma

The prevalence of fatty liver diseases has increased rapidly in recent years to about 25%worldwide.Fatty liver diseases are multi-faceted in pathogenesis,disease phenotype,and mechanism.It is important to understand disease pathogenesis and mechanism in order to develop effective and safe drug therapy for treating fatty liver diseases.Alcoholic fatty liver disease(AFLD,or alcohol associ-ated liver disease)and viral hepatitis have been the major causes of liver transplant,liver cancer,and death.

The gut's feeling on bile acid signaling in NAFLD

The gut to live axis plays a critical role in regulation of hepatic bile acid synthesis and metabolic homeostasis(1).Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease with a high prevalence of^35%in adults.NAFLD can progress from simple steatosis to non-alcoholic steatohepatitis(NASH),cirrhosis and hepatocellular carcinoma.NAFLD is associated with insulin resistance,obesity and type 2 diabetes.Bile acid-activated farnesoid X receptor(FXR)and G protein-coupled bile acid receptor-1(Gpbar-1,aka TGR5)have been shown to regulate lipid,glucose and energy metabolism and activation of FXR by agonists have been shown to improve hepatic metabolism and metabolic disorder in several mouse models of NASH(2).However,the role of bile acid signaling in pathogenesis and treatment of NASH is not clear.

Bile acid metabolism and signaling in liver diseases:Emerging trends of liver research and therapy

Conversion of cholesterol to bile acids is the only significant catabolic pathway for elimination of excessive cholesterol in our body.Bile acids have long been recognized as important physiological agents that facilitate absorption of dietary fats,steroids,drugs,and lipid soluble vitamins during the postprandial state.