Cholesterol 7α-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders

Jessica M Ferrell,Shannon Boehme,Feng Li,John Y.L Chiang

doi:10.1194/jlr.m064709

Jessica M Ferrell, Shannon Boehme + Show 2 more

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https://doi.org/10.1194/jlr.m064709

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Abstract

Cholesterol 7α-hydroxylase (CYP7A1) is the first and rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver. In addition to absorption and digestion of nutrients, bile acids play a critical role in the regulation of lipid, glucose, and energy homeostasis. We have backcrossed Cyp7a1(-/-) mice in a mixed B6/129Sv genetic background to C57BL/6J mice to generate Cyp7a1(-/-) mice in a near-pure C57BL/6J background. These mice survive well and have normal growth and a bile acid pool size ∼60% of WT mice. The expression of the genes in the alternative bile acid synthesis pathway are upregulated, resulting in a more hydrophilic bile acid composition with reduced cholic acid (CA). Surprisingly, Cyp7a1(-/-) mice have improved glucose sensitivity with reduced liver triglycerides and fecal bile acid excretion, but increased fecal fatty acid excretion and respiratory exchange ratio (RER) when fed a high-fat/high-cholesterol diet. Supplementing chow and Western diets with CA restored bile acid composition, reversed the glucose tolerant phenotype, and reduced the RER. Our current study points to a critical role of bile acid composition, rather than bile acid pool size, in regulation of glucose, lipid, and energy metabolism to improve glucose and insulin tolerance, maintain metabolic homeostasis, and prevent high-fat diet-induced metabolic disorders.

Highlights

Cholesterol 7 -hydroxylase (CYP7A1) is the first and rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver
Gallbladder bile acid composition analysis (Fig. 1A, lower panels) revealed Cyp7a1 / mice have markedly reduced taurocholic acid (TCA) (32%) and TDCA (6%) compared with WT mice (45% and 11%, respectively) and roughly doubled content of T- -muricholic acid (MCA) (25%) and TCDCA (7%) compared with WT (11% and 3%, respectively), while tauro- -MCA (T- -MCA) was not changed
Feeding Cyp7a1 / mice with 0.03% cholic acid (CA) resulted in further induction of Cyp8b1 and Cyp7b1, while Cyp27a1 and Shp gene expression were moderately increased compared with WT mice (Fig. 1B, upper right panel)

Summary

Introduction

Cholesterol 7 -hydroxylase (CYP7A1) is the first and rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver. In addition to absorption and digestion of nutrients, bile acids play a critical role in the regulation of lipid, glucose, and energy homeostasis. We have backcrossed Cyp7a1 / mice in a mixed B6/129Sv genetic background to C57BL/6J mice to generate Cyp7a1 / mice in a near-pure C57BL/6J background These mice survive well and have normal growth and a bile acid pool size 60% of WT mice. Cyp7a1 / mice have improved glucose sensitivity with reduced liver triglycerides and fecal bile acid excretion, but increased fecal fatty acid excretion and respiratory exchange ratio (RER) when fed a high-fat/high-cholesterol diet. Our current study points to a critical role of bile acid composition, rather than bile acid pool size, in regulation of glucose, lipid, and energy metabolism to improve glucose and insulin tolerance, maintain metabolic homeostasis, and prevent high-fat diet-induced metabolic disorders.—Ferrell, J.

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