title: Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1α-FXR signaling and alters systemic bile acid homeostasis.
abstract: OBJECTIVE
  Sirtuin 1 (SIRT1), the most conserved mammalian oxidized nicotinamide adenine dinucleotide-dependent protein deacetylase, is an important metabolic sensor in many tissues. However, little is known about its role in the small intestine, which absorbs and senses nutrients. We investigated the functions of intestinal SIRT1 in systemic bile acid and cholesterol metabolism in mice.
  
  
  METHODS
  SIRT1 was specifically deleted from the intestines of mice using the flox-Villin-Cre system (SIRT1 iKO mice). Intestinal and hepatic tissues were collected, and bile acid absorption was analyzed using the everted gut sac experiment. Systemic bile acid metabolism was studied in SIRT1 iKO and flox control mice placed on standard diets, diets containing 0.5% cholic acid or 1.25% cholesterol, or lithogenic diets.
  
  
  RESULTS
  SIRT1 iKO mice had reduced intestinal farnesoid X receptor (FXR) signaling via hepatocyte nuclear factor 1α (HNF-1α) compared with controls, which reduced expression of the bile acid transporter genes Asbt and Mcf2l (encodes Ost) and absorption of ileal bile acids. SIRT1 regulated HNF-1α/FXR signaling partially through dimerization cofactor of HNF-1a (Dcoh2) Dcoh2, which increases dimerization of HNF-1α. SIRT1 was found to deacetylate Dcoh2, promoting its interaction with HNF-1α and inducing DNA binding by HNF-1α. Intestine-specific deletion of SIRT1 increased hepatic bile acid biosynthesis, reduced hepatic accumulation of bile acids, and protected animals from liver damage from a diet high in levels of bile acids.
  
  
  CONCLUSIONS
  Intestinal SIRT1, a key nutrient sensor, is required for ileal bile acid absorption and systemic bile acid homeostasis in mice. We delineated the mechanism of metabolic regulation of HNF-1α/FXR signaling. Reagents designed to inhibit intestinal SIRT1 might be developed to treat bile acid-related diseases such as cholestasis.
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Nevzat
authors.initials: N
authors.lastname: Kazgan
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Mallikarjuna R
authors.initials: MR
authors.lastname: Metukuri
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Aparna
authors.initials: A
authors.lastname: Purushotham
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Section on Gastroenterology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Rao
authors.affiliation: The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois.
authors.forename: Sangkyu
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pratt-Hyatt
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lickteig
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Iván L
authors.initials: IL
authors.lastname: Csanaky
authors.affiliation: The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Section on Gastroenterology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dawson
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. Electronic address: lix3@niehs.nih.gov.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000378:metabolism; D019826:Cholic Acid / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism*; D006706:Homeostasis; D006836:Hydro-Lyases / Q000378:metabolism*; D007082:Ileum / Q000201:enzymology; D007408:Intestinal Absorption; D007422:Intestines / Q000201:enzymology*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000172:deficiency* / Q000235:genetics; D027981:Symporters / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D019826:Cholic Acid; D020662:Guanine Nucleotide Exchange Factors; D051538:Hepatocyte Nuclear Factor 1-alpha; D006836:Hydro-Lyases; D029363:Organic Anion Transporters, Sodium-Dependent; D018160:Receptors, Cytoplasmic and Nuclear; D064067:Rho Guanine Nucleotide Exchange Factors; D056564:Sirtuin 1; D027981:Symporters; D000099150:Receptor, Farnesoid X-Activated; C092132:Mcf2l protein, mouse; C071908:sodium-bile acid cotransporter; C470545:Sirt1 protein, mouse; C076392:pterin-4a-carbinolamine dehydratase
keywords: Bile Acid Synthesis; Cholestasis; Ileal Bile Acid Absorption; Liver Damage