title: Cyp8b1ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption.
abstract: Bile acids (BAs) are cholesterol derivatives that regulate lipid metabolism, through their dual abilities to promote lipid absorption and activate BA receptors. However, different BA species have varying abilities to perform these functions. Eliminating 12α-hydroxy BAs in mice viaCyp8b1knockout causes low body weight and improved glucose tolerance. The goal of this study was to determine mechanisms of low body weight inCyp8b1-/-mice. We challengedCyp8b1-/-mice with a Western-type diet and assessed body weight and composition. We measured energy expenditure, fecal calories, and lipid absorption and performed lipidomic studies on feces and intestine. We investigated the requirement for dietary fat in the phenotype using a fat-free diet.Cyp8b1-/-mice were resistant to Western diet-induced body weight gain, hepatic steatosis, and insulin resistance. These changes were associated with increased fecal calories, due to malabsorption of hydrolyzed dietary triglycerides. This was reversed by treating the mice with taurocholic acid, the major 12α-hydroxylated BA species. The improvements in body weight and steatosis were normalized by feeding mice a fat-free diet. The effects of BA composition on intestinal lipid handling are important for whole body energy homeostasis. Thus modulating BA composition is a potential tool for obesity or diabetes therapy.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertaggia
authors.affiliation: Diabetes Department, Merck Research Laboratories, Kenilworth, New Jersey; and.
authors.forename: Kristian K
authors.initials: KK
authors.lastname: Jensen
authors.affiliation: Diabetes Department, Merck Research Laboratories, Kenilworth, New Jersey; and.
authors.forename: Jose
authors.initials: J
authors.lastname: Castro-Perez
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York.|Denali Therapeutics, Incorporated, South San Francisco, California.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York.
authors.forename: Robin B
authors.initials: RB
authors.lastname: Chan
authors.affiliation: Diabetes Department, Merck Research Laboratories, Kenilworth, New Jersey; and.
authors.forename: Liangsu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York; rah2130@cumc.columbia.edu.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Haeusler
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D059305:Diet, High-Fat; D066273:Diet, Western / Q000009:adverse effects*; D004041:Dietary Fats / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D007408:Intestinal Absorption / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics*; D015430:Weight Gain / Q000235:genetics*
chemical_list: D001647:Bile Acids and Salts; D004041:Dietary Fats; D013253:Steroid 12-alpha-Hydroxylase
keywords: bile acids; diabetes; lipid absorption; obesity; triglyceride