Soaping Up Type 2 Diabetes With Bile Acids?: The Link Between Glucose and Bile Acid Metabolism in Humans Tightens: Quality Matters!

Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently – despite elusive mechanisms of action – bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5.

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Bile Acid Metabolism and the Pathogenesis of Type 2 Diabetes

Current Diabetes Reports ◽

10.1007/s11892-011-0187-x ◽

2011 ◽

Vol 11 (3) ◽

pp. 160-166 ◽

Cited By ~ 138

Author(s):

Janne Prawitt ◽

Sandrine Caron ◽

Bart Staels

Keyword(s):

Type 2 Diabetes ◽

Bile Acid ◽

Acid Metabolism ◽

Bile Acid Metabolism

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Abstract 49: The Transcriptional Repressor MafG Regulates Cholesterol Catabolism

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.49 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Thomas Q de Aguiar Vallim ◽

Elizabeth J Tarling ◽

Hannah Ahn ◽

Lee R Hagey ◽

Casey E Romanoski ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Metabolic Diseases ◽

Cholesterol Metabolism ◽

Transcriptional Repressor ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Bile Acid Metabolism ◽

Biliary Bile Acid

Elevated circulating cholesterol levels is a major risk factor for cardiovascular diseases (CVD), and therefore understanding pathways that affect cholesterol metabolism are important for potential treatment of CVD. The major route for cholesterol excretion is through its catabolism to bile acids. Specific bile acids are also potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis ( Cyp7a1 , Cyp8b1 ) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway, and modifies the biliary bile acid composition. In contrast, MafG loss-of-function studies cause de-repression of the bile acid genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-Seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR. The identification of this pathway will likely have important implications in metabolic diseases.

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Identification of bile acids in the serum and urine in cholestasis. Evidence for 6α-hydroxylation of bile acids in man

Biochemical Journal ◽

10.1042/bj1540507 ◽

1976 ◽

Vol 154 (2) ◽

pp. 507-516 ◽

Cited By ~ 88

Author(s):

J A. Summerfield ◽

B H. Billing ◽

C H. L. Shackleton

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Gas Chromatography Mass Spectrometry ◽

Acid Mixture ◽

Bile Acid Metabolism ◽

Hyodeoxycholic Acid ◽

Normal Man ◽

Hyocholic Acid ◽

Sulphate Conjugate

In this qualitative study of the pattern of bile acid excretion in cholestasis, methods are described for the isolation of bile acids from large volumes of urine and plasma. The bile acids were subjected to a group separation and identified by combined gas chromatography-mass spectrometry. The techniques were developed to allow identification of the minor components of the bile acid mixture. Four bile acids that have not previously been described in human urine and plasma were detected, namely 3β, 7α-dihydroxy-5β-cholan-24-oic acid, 3α, 6α-dihydroxy-5β-cholan-24-oic acid (hyodeoxycholic acid), 3α, 6α, 7α-trihydroxy-5β-cholan-24-oic acid (hyocholic acid) and 3α, 7β, 12α-trihydroxy-5β-cholan-24-oic acid. In addition three C27 steroids were found; 26-hydroxycholesterol and a trihydroxy cholestane, probably 5 β-cholestane-3α, 7α, 26-triol were found in the sulphate fraction of plasma and urine. In the plasma sample, a sulphate conjugate of 24-hydroxycholesterol was found. The presence of these compounds probably reflects the existence of further pathways for bile acid metabolism. It is not yet known whether this is a consequence of the cholestasis or whether they are also present in normal man, at much lower concentrations.

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