Bile acid conjugation deficiency causes hypercholanemia, hyperphagia, islet dysfunction, and gut dysbiosis in mice.

Autor: Alrehaili BD; Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.; Graduate Program of Biomedical Sciences, Kent State University, Kent, Ohio, USA.; Department of Pharmacology and Toxicology, Pharmacy College, Taibah University, Medina, Saudi Arabia., Lee M; Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA., Takahashi S; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Novak R; Department of Pathology, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA., Rimal B; Department of Molecular Toxicology, The Pennsylvania State University, University Park, Pennsylvania, USA., Boehme S; Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA., Trammell SAJ; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Grevengoed TJ; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Kumar D; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NA, USA., Alnouti Y; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NA, USA., Chiti K; Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio, USA., Wang X; Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio, USA., Patterson AD; Department of Molecular Toxicology, The Pennsylvania State University, University Park, Pennsylvania, USA., Chiang JYL; Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA., Gonzalez FJ; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA., Lee YK; Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.; Graduate Program of Biomedical Sciences, Kent State University, Kent, Ohio, USA.
Jazyk: angličtina
Zdroj: Hepatology communications [Hepatol Commun] 2022 Oct; Vol. 6 (10), pp. 2765-2780. Date of Electronic Publication: 2022 Jul 22.
DOI: 10.1002/hep4.2041
Abstrakt: Bile acid-CoA: amino acid N-acyltransferase (BAAT) catalyzes bile acid conjugation, the last step in bile acid synthesis. BAAT gene mutation in humans results in hypercholanemia, growth retardation, and fat-soluble vitamin insufficiency. The current study investigated the physiological function of BAAT in bile acid and lipid metabolism using Baat -/- mice. The bile acid composition and hepatic gene expression were analyzed in 10-week-old Baat -/- mice. They were also challenged with a westernized diet (WD) for additional 15 weeks to assess the role of BAAT in bile acid, lipid, and glucose metabolism. Comprehensive lab animal monitoring system and cecal 16S ribosomal RNA gene sequencing were used to evaluate the energy metabolism and microbiome structure of the mice, respectively. In Baat -/- mice, hepatic bile acids were mostly unconjugated and their levels were significantly increased compared with wild-type mice. Bile acid polyhydroxylation was markedly up-regulated to detoxify unconjugated bile acid accumulated in Baat -/- mice. Although the level of serum marker of bile acid synthesis, 7α-hydroxy-4-cholesten-3-one, was higher in Baat -/- mice, their bile acid pool size was smaller. When fed a WD, the Baat -/- mice showed a compromised body weight gain and impaired insulin secretion. The gut microbiome of Baat -/- mice showed a low level of sulfidogenic bacteria Bilophila. Conclusion: Mouse BAAT is the major taurine-conjugating enzyme. Its deletion protected the animals from diet-induced obesity, but caused glucose intolerance. The gut microbiome of the Baat -/- mice was altered to accommodate the unconjugated bile acid pool.
(© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
Externí odkaz: