Beyond intestinal soap—bile acids in metabolic control

• Published in: Nature reviews. Endocrinology Vol. 10; no. 8; pp. 488 - 498
• Main Authors: Kuipers, Folkert, Bloks, Vincent W., Groen, Albert K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2014; Nature Publishing Group
• Subjects: 692/308/575; 692/699/2743/137/773; 692/700/565/1436; Allylamine - analogs & derivatives; Allylamine - therapeutic use; Animals; Anticholesteremic Agents - pharmacology; Bile; Bile acids; Bile Acids and Salts - biosynthesis; Bile Acids and Salts - physiology; Blood Glucose - drug effects; Blood Glucose - metabolism; Cholesterol; Colesevelam Hydrochloride; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Endocrinology; Energy Metabolism - drug effects; Fibroblast Growth Factors - physiology; Glucose; Glucose metabolism; Glycated Hemoglobin A - metabolism; Health aspects; Humans; Insulin; Insulin Resistance; Ligands; Lipid Metabolism - drug effects; Lipids; Liver; Male; Medicine & Public Health; Metabolic disorders; Mice; Physiological aspects; Physiology; Proteins; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - physiology; Receptors, G-Protein-Coupled - physiology; review-article; Signal Transduction - drug effects; Netherlands
• ISSN: 1759-5029; 1759-5037
• DOI: 10.1038/nrendo.2014.60

Key Points Bile acids are amphipathic steroids derived from cholesterol that serve important physiological functions such as bile formation and intestinal fat absorption that are dependent on their detergent nature The discovery of farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (TGR5) as bile acid receptors that regulate glucose, lipid and energy metabolism has highlighted bile acids as key players in metabolic control Modulators of bile acid receptors have been developed as potential treatments for cholestatic liver diseases and metabolic diseases; organ-specific and/or gene-cluster-selective modulators are expected in the near future Type 2 diabetes mellitus (T2DM) is accompanied by a shift in primary bile acid synthesis towards cholic acid and a corresponding increase in the secondary bile acid deoxycholic acid Beneficial effects of bile acid sequestrants on glucose metabolism in patients with T2DM could reflect changed compartmentalization of the bile acid pool that modifies intestinal bile acid signalling In this article, Kuipers and colleagues review how bile acids modulate glucose and lipid metabolism. The authors discuss the mechanisms by which bile acids, agonists of bile acid signalling pathways and bile acid sequestrants influence glucose levels in animal models and patients with insulin resistance and type 2 diabetes mellitus and how altered bile acid metabolism might contribute to the beneficial effects of bariatric surgery. Over the past decade, it has become apparent that bile acids are involved in a host of activities beyond their classic functions in bile formation and fat absorption. The identification of the farnesoid X receptor (FXR) as a nuclear receptor directly activated by bile acids and the discovery that bile acids are also ligands for the membrane-bound, G-protein coupled bile acid receptor 1 (also known as TGR5) have opened new avenues of research. Both FXR and TGR5 regulate various elements of glucose, lipid and energy metabolism. Consequently, a picture has emerged of bile acids acting as modulators of (postprandial) metabolism. Therefore, strategies that interfere with either bile acid metabolism or signalling cascades mediated by bile acids may represent novel therapeutic approaches for metabolic diseases. Synthetic modulators of FXR have been designed and tested, primarily in animal models. Furthermore, the use of bile acid sequestrants to reduce plasma cholesterol levels has unexpected benefits. For example, treatment of patients with type 2 diabetes mellitus (T2DM) with sequestrants causes substantial reductions in plasma levels of glucose and HbA 1c . This Review aims to provide an overview of the molecular mechanisms by which bile acids modulate glucose and energy metabolism, particularly focusing on the glucose-lowering actions of bile acid sequestrants in insulin resistant states and T2DM.