Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1α-FXR signaling and alters systemic bile acid homeostasis

Nevzat Kazgan, Mallikarjuna R. Metukuri, Aparna Purushotham, Jing Lu, Anuradha Rao, Sangkyu Lee, Matthew Pratt-Hyatt, Andrew Lickteig, Iván L. Csanaky, Yingming Zhao, Paul A. Dawson, Xiaoling Li

Research output: Contribution to journalArticle

Abstract

Background & Aims 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.

Original languageEnglish (US)
Pages (from-to)1006-1016
Number of pages11
JournalGastroenterology
Volume146
Issue number4
DOIs
StatePublished - 2014
Externally publishedYes

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Hepatocyte Nuclear Factor 1
Sirtuin 1
Bile Acids and Salts
Intestines
Homeostasis
Diet
Liver
Dimerization
Cholesterol
Cholic Acid
Food
Cholestasis
NAD
Small Intestine

Keywords

  • Bile Acid Synthesis
  • Cholestasis
  • Ileal Bile Acid Absorption
  • Liver Damage

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1α-FXR signaling and alters systemic bile acid homeostasis. / Kazgan, Nevzat; Metukuri, Mallikarjuna R.; Purushotham, Aparna; Lu, Jing; Rao, Anuradha; Lee, Sangkyu; Pratt-Hyatt, Matthew; Lickteig, Andrew; Csanaky, Iván L.; Zhao, Yingming; Dawson, Paul A.; Li, Xiaoling.

In: Gastroenterology, Vol. 146, No. 4, 2014, p. 1006-1016.

Research output: Contribution to journalArticle

Kazgan, N, Metukuri, MR, Purushotham, A, Lu, J, Rao, A, Lee, S, Pratt-Hyatt, M, Lickteig, A, Csanaky, IL, Zhao, Y, Dawson, PA & Li, X 2014, 'Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1α-FXR signaling and alters systemic bile acid homeostasis', Gastroenterology, vol. 146, no. 4, pp. 1006-1016. https://doi.org/10.1053/j.gastro.2013.12.029
Kazgan, Nevzat ; Metukuri, Mallikarjuna R. ; Purushotham, Aparna ; Lu, Jing ; Rao, Anuradha ; Lee, Sangkyu ; Pratt-Hyatt, Matthew ; Lickteig, Andrew ; Csanaky, Iván L. ; Zhao, Yingming ; Dawson, Paul A. ; Li, Xiaoling. / Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1α-FXR signaling and alters systemic bile acid homeostasis. In: Gastroenterology. 2014 ; Vol. 146, No. 4. pp. 1006-1016.
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abstract = "Background & Aims 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.",
keywords = "Bile Acid Synthesis, Cholestasis, Ileal Bile Acid Absorption, Liver Damage",
author = "Nevzat Kazgan and Metukuri, {Mallikarjuna R.} and Aparna Purushotham and Jing Lu and Anuradha Rao and Sangkyu Lee and Matthew Pratt-Hyatt and Andrew Lickteig and Csanaky, {Iv{\'a}n L.} and Yingming Zhao and Dawson, {Paul A.} and Xiaoling Li",
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T1 - Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1α-FXR signaling and alters systemic bile acid homeostasis

AU - Kazgan, Nevzat

AU - Metukuri, Mallikarjuna R.

AU - Purushotham, Aparna

AU - Lu, Jing

AU - Rao, Anuradha

AU - Lee, Sangkyu

AU - Pratt-Hyatt, Matthew

AU - Lickteig, Andrew

AU - Csanaky, Iván L.

AU - Zhao, Yingming

AU - Dawson, Paul A.

AU - Li, Xiaoling

PY - 2014

Y1 - 2014

N2 - Background & Aims 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.

AB - Background & Aims 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.

KW - Bile Acid Synthesis

KW - Cholestasis

KW - Ileal Bile Acid Absorption

KW - Liver Damage

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