title: The Role of Sirt1 in Bile Acid Regulation during Calorie Restriction in Mice.
abstract: Sirtuin 1 (Sirt1) is an NAD+-dependent protein deacetylase that is proposed to mediate many health-promoting effects of calorie restriction (CR). We recently reported that short-term CR increased the bile acid (BA) pool size in mice, likely due to increased BA synthesis in liver. Given the important role of Sirt1 in the regulation of glucose, lipid, as well as BA metabolism, we hypothesized that the CR-induced increase in BAs is Sirt1-dependent. To address this, the present study utilized genetically-modified mice that were Sirt1 loss of function (liver knockout, LKO) or Sirt1 gain of function (whole body-transgenic, TG). Three genotypes of mice (Sirt1-LKO, wild-type, and Sirt1-TG) were each randomly divided into ad libitum or 40% CR feeding for one month. BAs were extracted from various compartments of the enterohepatic circulation, followed by BA profiling by UPLC-MS/MS. CR increased the BA pool size and total BAs in serum, gallbladder, and small intestine. The CR-induced increase in BA pool size correlated with the tendency of increase in the expression of the rate-limiting BA-synthetic enzyme Cyp7a1. However, in contrast to the hypothesis, the CR-induced increase in BA pool size and Cyp7a1 expression was still observed with ablated expression of Sirt1 in liver, and completely suppressed with whole-body overexpression of Sirt1. Furthermore, in terms of BA composition, CR increased the ratio of 12α-hydroxylated BAs regardless of Sirt1 genotypes. In conclusion, the CR-induced alterations in BA pool size, BA profiles, and expression of BA-related genes do not appear to be dependent on Sirt1.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America; Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province, People's Republic of China, 150081.
authors.forename: Zidong Donna
authors.initials: ZD
authors.lastname: Fu
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States of America.
authors.forename: Julia Yue
authors.initials: JY
authors.lastname: Cui
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, United States of America.
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport; D001835:Body Weight; D031204:Caloric Restriction; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D007082:Ileum / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D056564:Sirtuin 1