Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity.

Title

Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity.

Creator

Li Tiangang; Francl Jessica M; Boehme Shannon; Ochoa Adrian; Zhang Youcai; Klaassen Curtis D; Erickson Sandra K; Chiang John Y L

Publisher

The Journal of biological chemistry

Date

2012
2012-01

Description

Bile acids facilitate postprandial absorption of nutrients. Bile acids also activate the farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5 and play a major role in regulating lipid, glucose, and energy metabolism. Transgenic expression of cholesterol 7alpha-hydroxylase (CYP7A1) prevented high fat diet-induced diabetes and obesity in mice. In this study, we investigated the nutrient effects on bile acid synthesis. Refeeding of a chow diet to fasted mice increased CYP7A1 expression, bile acid pool size, and serum bile acids in wild type and humanized CYP7A1-transgenic mice. Chromatin immunoprecipitation assays showed that glucose increased histone acetylation and decreased histone methylation on the CYP7A1 gene promoter. Refeeding also induced CYP7A1 in fxr-deficient mice, indicating that FXR signaling did not play a role in postprandial regulation of bile acid synthesis. In streptozocin-induced type I diabetic mice and genetically obese type II diabetic ob/ob mice, hyperglycemia increased histone acetylation status on the CYP7A1 gene promoter, leading to elevated basal Cyp7a1 expression and an enlarged bile acid pool with altered bile acid composition. However, refeeding did not further increase CYP7A1 expression in diabetic mice. In summary, this study demonstrates that glucose and insulin are major postprandial factors that induce CYP7A1 gene expression and bile acid synthesis. Glucose induces CYP7A1 gene expression mainly by epigenetic mechanisms. In diabetic mice, CYP7A1 chromatin is hyperacetylated, and fasting to refeeding response is impaired and may exacerbate metabolic disorders in diabetes.

Subject

*Gene Expression Regulation; Animals; Bile Acids and Salts/*biosynthesis; Cholesterol 7-alpha-Hydroxylase/genetics/*metabolism; Cytoplasmic and Nuclear/genetics/metabolism; Diabetes Mellitus; Dietary Fats/administration & dosage/adverse effects; Enzymologic; Epigenesis; Experimental/genetics/*metabolism; Fasting/metabolism; Genetic/genetics; Glucose/*metabolism/pharmacology; Insulin/*metabolism; Mice; Obesity/etiology/genetics/*metabolism; Postprandial Period/genetics; Receptors; Sweetening Agents/pharmacology; Transgenic

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

1861–1873

Issue

3

Volume

287

Citation

Li Tiangang; Francl Jessica M; Boehme Shannon; Ochoa Adrian; Zhang Youcai; Klaassen Curtis D; Erickson Sandra K; Chiang John Y L, “Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity.,” NEOMED Bibliography Database, accessed May 14, 2021, https://neomed.omeka.net/items/show/4063.

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