title: Cholesterol 7α-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders.
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.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Ferrell
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH.
authors.forename: Shannon
authors.initials: S
authors.lastname: Boehme
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH jchiang@neomed.edu.
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D045853:Exhalation / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008659:Metabolic Diseases / Q000235:genetics* / Q000378:metabolism; D051379:Mice
chemical_list: D001647:Bile Acids and Salts; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D005947:Glucose
keywords: bile acids and salt/metabolism; cholesterol/diet; lipids; liver