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Genetic deletion of hepatic NCOR1 protects from atherosclerosis by promoting alternative bile acid-metabolism and sterol excretion.
Geiger, Martin; Oppi, Sara; Nusser-Stein, Stefanie; Costantino, Sarah; Mohammed, Shafeeq Ahmed; Gorica, Era; Hoogerland, Joanne A; Matter, Christian M; Guillaumon, Ana T; Ruschitzka, Frank; Paneni, Francesco; Oosterveer, Maaike H; Stein, Sokrates.
Afiliación
  • Geiger M; Center for Translational and Experimental Cardiology, University of Zurich, Schlieren, Switzerland. martinandreas.geiger@uzh.ch.
  • Oppi S; Center for Translational and Experimental Cardiology, University of Zurich, Schlieren, Switzerland.
  • Nusser-Stein S; Center for Translational and Experimental Cardiology, University of Zurich, Schlieren, Switzerland.
  • Costantino S; Center for Translational and Experimental Cardiology, University of Zurich, Schlieren, Switzerland.
  • Mohammed SA; Center for Translational and Experimental Cardiology, University of Zurich, Schlieren, Switzerland.
  • Gorica E; Center for Translational and Experimental Cardiology, University of Zurich, Schlieren, Switzerland.
  • Hoogerland JA; Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Matter CM; Center for Translational and Experimental Cardiology, University of Zurich, Schlieren, Switzerland.
  • Guillaumon AT; Department of Research and Education, University Hospital Zurich, CH-8091, Zurich, Switzerland.
  • Ruschitzka F; Vascular Diseases Discipline, Clinics Hospital of the University of Campinas, Campinas, Brazil.
  • Paneni F; Center for Translational and Experimental Cardiology, University of Zurich, Schlieren, Switzerland.
  • Oosterveer MH; Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, CH-8091, Zurich, Switzerland.
  • Stein S; Center for Translational and Experimental Cardiology, University of Zurich, Schlieren, Switzerland.
Cardiovasc Diabetol ; 22(1): 144, 2023 06 22.
Article en En | MEDLINE | ID: mdl-37349757
BACKGROUND: The nuclear receptor corepressor 1 (NCOR1) plays an important role in the regulation of gene expression in immunometabolic conditions by connecting chromatin-modifying enzymes, coregulators and transcription factors. NCOR1 has been shown to be involved in cardiometabolic diseases. Recently, we demonstrated that the deletion of macrophage NCOR1 aggravates atherosclerosis by promoting CD36-triggered foam cell formation via PPARG derepression. PURPOSE: Since NCOR1 modulates the function of several key regulators involved in hepatic lipid and bile acid metabolism, we hypothesized that its deletion in hepatocytes alters lipid metabolism and atherogenesis. METHODS: To test this hypothesis, we generated hepatocyte-specific Ncor1 knockout mice on a Ldlr-/- background. Besides assessing the progression of the disease in thoracoabdominal aortae en face, we analyzed hepatic cholesterol and bile acid metabolism at expression and functional levels. RESULTS: Our data demonstrate that liver-specific Ncor1 knockout mice on an atherosclerosis-prone background develop less atherosclerotic lesions than controls. Interestingly, under chow diet, plasma cholesterol levels of liver-specific Ncor1 knockout mice were slightly higher compared to control, but strongly reduced compared to control mice after feeding them an atherogenic diet for 12 weeks. Moreover, the hepatic cholesterol content was decreased in liver-specific Ncor1 knockout compared to control mice. Our mechanistic data revealed that NCOR1 reprograms the synthesis of bile acids towards the alternative pathway, which in turn reduce bile hydrophobicity and enhances fecal cholesterol excretion. CONCLUSIONS: Our data suggest that hepatic Ncor1 deletion in mice decreases atherosclerosis development by reprograming bile acid metabolism and enhancing fecal cholesterol excretion.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esteroles / Aterosclerosis Límite: Animals Idioma: En Revista: Cardiovasc Diabetol Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA / ENDOCRINOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esteroles / Aterosclerosis Límite: Animals Idioma: En Revista: Cardiovasc Diabetol Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA / ENDOCRINOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido