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John Y L Chiang – 1st expert on this subject based on the ideXlab platform
Bile Acid metabolism in liver pathobiologyGene Expression, 2018Co-Authors: John Y L Chiang, Jessica M FerrellAbstract:
: Bile Acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain Bile Acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and Bile Acid toxicity. Bile Acid metabolism is tightly regulated by Bile Acid synthesis in the liver and Bile Acid biotransformation in the intestine. Bile Acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled Bile Acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of Bile Acids, Bile Acid pool size, and Bile Acid composition. Bile Acids control gut bacteria overgrowth, and gut bacteria metabolize Bile Acids to regulate host metabolism. Alteration of Bile Acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in Bile Acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of Bile Acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile Acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders.
g protein coupled Bile Acid receptor plays a key role in Bile Acid metabolism and fasting induced hepatic steatosis in miceHepatology, 2017Co-Authors: Ajay C Donepudi, Feng Li, Shannon Boehme, John Y L ChiangAbstract:
Bile Acids are signaling molecules that play a critical role in regulation of hepatic metabolic homeostasis by activating nuclear farnesoid X receptor (Fxr) and membrane G-protein-coupled receptor (Tgr5). The role of FXR in regulation of Bile Acid synthesis and hepatic metabolism has been studied extensively. However, the role of TGR5 in hepatic metabolism has not been explored. The liver plays a central role in lipid metabolism and impaired response to fasting and feeding contributes to steatosis and non-alcoholic fatty liver and obesity. We have performed a detailed analysis of gallbladder Bile Acid and lipid metabolism in Tgr5-/- mice in both free-fed and fasted conditions. Lipid profiles of serum, liver and adipose tissues, Bile Acid composition, energy metabolism, and mRNA and protein expression of the genes involved in lipid metabolism were analyzed. Results showed that deficiency of the Tgr5 gene in mice alleviated fasting-induced hepatic lipid accumulation. Expression of liver oxysterol 7α-hydroxylase (Cyp7b1) in the alternative Bile Acid synthesis pathway was reduced. Analysis of gallbladder Bile Acid composition showed marked increase of tauro-cholic Acid and decrease of tauro-α and β-muricholic Acid in Tgr5-/- mice. Tgr5-/- mice had increased hepatic fatty Acid oxidation rate and decreased hepatic fatty Acid uptake. Interestingly, fasting induction of fibroblast growth factor 21 (Fgf21) in liver was attenuated. In addition, fasted Tgr5-/- mice had increased activation of hepatic growth hormone-signal transducer and activator of transcription 5 (GH-Stat5) signaling compared to wild type mice. Conclusion: This study suggests that TGR5 may play a role in determining Bile Acid composition and in fasting-induced hepatic steatosis through a novel mechanism involving activation of the GH-Stat5 signaling pathway. This article is protected by copyright. All rights reserved.
Bile Acid metabolism and signalingComprehensive Physiology, 2013Co-Authors: John Y L ChiangAbstract:
Bile Acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile Acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to Bile Acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of Bile Acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic Bile Acids may cause inflammation, apoptosis, and cell death. On the other hand, Bile Acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in Bile Acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile Acids, Bile Acid derivatives, and Bile Acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans.
Paul A Dawson – 2nd expert on this subject based on the ideXlab platform
animal models to study Bile Acid metabolismBiochimica et Biophysica Acta, 2019Co-Authors: Jianing Li, Paul A DawsonAbstract:
Abstract The use of animal models, particularly genetically modified mice, continues to play a critical role in studying the relationship between Bile Acid metabolism and human liver disease. Over the past 20 years, these studies have been instrumental in elucidating the major pathways responsible for Bile Acid biosynthesis and enterohepatic cycling, and the molecular mechanisms regulating those pathways. This work also revealed Bile Acid differences between species, particularly in the composition, physicochemical properties, and signaling potential of the Bile Acid pool. These species differences may limit the ability to translate findings regarding Bile Acid-related disease processes from mice to humans. In this review, we focus primarily on mouse models and also briefly discuss dietary or surgical models commonly used to study the basic mechanisms underlying Bile Acid metabolism. Important phenotypic species differences in Bile Acid metabolism between mice and humans are highlighted.
Bile Acid MetabolismBiochemistry of Lipids Lipoproteins and Membranes, 2015Co-Authors: Paul A DawsonAbstract:
Bile Acids are synthesised from cholesterol by the liver and are the major end products of cholesterol catabolism. Bile Acid homoeostasis is dependent on hepatic de novo synthesis and an intact enterohepatic circulation, by means of which Bile Acids emptied into the small intestine are efficiently reabsorbed and sent back to the liver for resecretion into Bile. As such, most of the biliary Bile Acids were previously secreted and had undergone enterohepatic cycling. In addition to acting as detergents to facilitate digestion and absorption of dietary lipids, Bile Acids play important roles in cholesterol homoeostasis, in hepatic Bile formation and biliary excretion of lipids, and as signalling molecules to regulate lipid and glucose metabolism. This chapter reviews the pathways for biosynthesis, transport and metabolism of Bile Acids. The regulation of Bile Acid homoeostasis and their role as signalling molecules is also discussed.
Role of the intestinal Bile Acid transporters in Bile Acid and drug disposition.Handbook of experimental pharmacology, 2010Co-Authors: Paul A DawsonAbstract:
Membrane transporters expressed by the hepatocyte and enterocyte play critical roles in maintaining the enterohepatic circulation of Bile Acids, an effective recycling and conservation mechanism that largely restricts these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments. In doing so, the hepatic and enterocyte transport systems ensure a continuous supply of Bile Acids to be used repeatedly during the digestion of multiple meals throughout the day. Absorption of Bile Acids from the intestinal lumen and export into the portal circulation is mediated by a series of transporters expressed on the enterocyte apical and basolateral membranes. The ileal apical sodium-dependent Bile Acid cotransporter (abbreviated ASBT; gene symbol, SLC10A2) is responsible for the initial uptake of Bile Acids across the enterocyte brush border membrane. The Bile Acids are then efficiently shuttled across the cell and exported across the basolateral membrane by the heteromeric Organic Solute Transporter, OSTα–OSTβ. This chapter briefly reviews the tissue expression, physiology, genetics, pathophysiology, and transport properties of the ASBT and OSTα–OSTβ. In addition, the chapter discusses the relationship between the intestinal Bile Acid transporters and drug metabolism, including development of ASBT inhibitors as novel hypocholesterolemic or hepatoprotective agents, prodrug targeting of the ASBT to increase oral bioavailability, and involvement of the intestinal Bile Acid transporters in drug absorption and drug–drug interactions.
Tiangang Li – 3rd expert on this subject based on the ideXlab platform
Bile Acid metabolism and signaling in cholestasis inflammation and cancerAdvances in pharmacology (San Diego), 2015Co-Authors: Tiangang Li, Udayan ApteAbstract:
Abstract Bile Acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in Bile Acid synthesis. Bile Acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating Bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid-soluble vitamins. Bile Acid synthesis, transport, and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired Bile flow leads to accumulation of Bile Acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis, and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that Bile Acids act as signaling molecules that regulate various cellular processes. The Bile Acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of Bile Acid, drug, and xenobiotic metabolism. In cholestasis, these Bile Acid-activated receptors regulate a network of genes involved in Bile Acid synthesis, conjugation, transport, and metabolism to alleviate Bile Acid-induced inflammation and injury. Additionally, Bile Acids are known to regulate cell growth and proliferation, and altered Bile Acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate Bile Acid homeostasis and detoxification during cholestasis, and the roles of Bile Acids in the initiation and regulation of hepatic inflammation, regeneration, and carcinogenesis.
nuclear receptors in Bile Acid metabolismDrug Metabolism Reviews, 2013Co-Authors: Tiangang Li, John Y L ChiangAbstract:
Bile Acids are signaling molecules that activate nuclear receptors, such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism. These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in Bile Acid and drug metabolism in the digestive system. Integration of Bile Acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity. Bile–Acid–based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease.
Bile Acid signaling in liver metabolism and diseasesJournal of Lipids, 2012Co-Authors: Tiangang Li, John Y L ChiangAbstract:
Obesity, diabetes, and metabolic syndromes are increasingly recognized as health concerns worldwide. Overnutrition and insulin resistance are the major causes of diabetic hyperglycemia and hyperlipidemia in humans. Studies in the past decade provide evidence that Bile Acids are not just biological detergents facilitating gut nutrient absorption, but also important metabolic regulators of glucose and lipid homeostasis. Pharmacological alteration of Bile Acid metabolism or Bile Acid signaling pathways such as using Bile Acid receptor agonists or Bile Acid binding resins may be a promising therapeutic strategy for the treatment of obesity and diabetes. On the other hand, Bile Acid signaling is complex, and the molecular mechanisms mediating the Bile Acid effects are still not completely understood. This paper will summarize recent advances in our understanding of Bile Acid signaling in regulation of glucose and lipid metabolism, and the potentials of developing novel therapeutic strategies that target Bile Acid metabolism for the treatment of metabolic disorders.