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FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption.
Clifford, Bethan L; Sedgeman, Leslie R; Williams, Kevin J; Morand, Pauline; Cheng, Angela; Jarrett, Kelsey E; Chan, Alvin P; Brearley-Sholto, Madelaine C; Wahlström, Annika; Ashby, Julianne W; Barshop, William; Wohlschlegel, James; Calkin, Anna C; Liu, Yingying; Thorell, Anders; Meikle, Peter J; Drew, Brian G; Mack, Julia J; Marschall, Hanns-Ulrich; Tarling, Elizabeth J; Edwards, Peter A; de Aguiar Vallim, Thomas Q.
Afiliação
  • Clifford BL; Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Sedgeman LR; Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Williams KJ; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Lipidomics Core Facility, Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Morand P; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Cheng A; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Jarrett KE; Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Chan AP; Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Brearley-Sholto MC; Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Wahlström A; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • Ashby JW; Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Barshop W; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Wohlschlegel J; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Calkin AC; Lipid Metabolism & Cardiometabolic Disease Laboratory, Baker Heart & Diabetes Institute, Melbourne, VIC, Australia; Central Clinical School, Monash University, Melbourne, VIC, Australia.
  • Liu Y; Lipid Metabolism & Cardiometabolic Disease Laboratory, Baker Heart & Diabetes Institute, Melbourne, VIC, Australia; Molecular Metabolism & Ageing Laboratory, Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.
  • Thorell A; Karolinska Institutet, Department of Clinical Science, Danderyd Hospital and Department of Surgery, Ersta Hospital, Stockholm, Sweden.
  • Meikle PJ; Metabolomics Laboratory, Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.
  • Drew BG; Central Clinical School, Monash University, Melbourne, VIC, Australia; Molecular Metabolism & Ageing Laboratory, Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.
  • Mack JJ; Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Marschall HU; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • Tarling EJ; Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Edwards PA; Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Molecular Biology Institute, University of Cali
  • de Aguiar Vallim TQ; Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCL
Cell Metab ; 33(8): 1671-1684.e4, 2021 08 03.
Article em En | MEDLINE | ID: mdl-34270928
ABSTRACT
FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids. Here, we show that FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXR activation in mice or humans specifically reduces hepatic levels of mono- and polyunsaturated fatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repression of Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAs are mediated by decreases in lipid absorption. Replenishing bile acids in the diet prevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXR reduces absorption via decreased bile acids. We used tissue-specific FXR KO mice to show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption. Together, our studies establish two distinct pathways by which FXR regulates hepatic lipids.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ácidos e Sais Biliares / Hepatopatia Gordurosa não Alcoólica Idioma: En Ano de publicação: 2021 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ácidos e Sais Biliares / Hepatopatia Gordurosa não Alcoólica Idioma: En Ano de publicação: 2021 Tipo de documento: Article