TY - JOUR
T1 - Genetic deletion of hepatic NCOR1 protects from atherosclerosis by promoting alternative bile acid-metabolism and sterol excretion
AU - Geiger, Martin
AU - Oppi, Sara
AU - Nusser-Stein, Stefanie
AU - Costantino, Sarah
AU - Mohammed, Shafeeq Ahmed
AU - Gorica, Era
AU - Hoogerland, Joanne A.
AU - Matter, Christian M.
AU - Guillaumon, Ana T.
AU - Ruschitzka, Frank
AU - Paneni, Francesco
AU - Oosterveer, Maaike H.
AU - Stein, Sokrates
N1 - Funding Information:
This research was funded by the Swiss National Science Foundation (Grant number 310030_197557 to FP). This work was supported by grants from the Swiss National Science Foundation (Grant number PZOOP3_161521 to SS), the Novartis Foundation for medical-biological Research (Grant number 16B103 to SS), the Olga-Mayenfisch Foundation to SS, the OPO foundation (Grant number 2018-0054 to SS), the Swiss Heart Foundation to SNS and SS. MHO holds a Rosalind Franklin Fellowship from the University of Groningen. MG holds a Sandwich-Doctorate Grant financed by the CAPES (Coordination for the Improvement of Higher Education Personnel - Grant number 88887.694869/2022-00), in Brazil.
Funding Information:
We thank Johan Auwerx and Kristina Schoonjans from the École Polytechnique Fédérale de Lausanne for providing the floxed Ncor1 mice, Trijnie Bos from the University Medical Center Groningen for excellent technical support with lipid analyses, Wino Wijnen from WiWright (https://wiwright.com/) for professional image acquisition of the stained en face aortae and Professor Giuseppe Danilo Norata from the University of Milan for the valuable comments and inputs to the final version of the manuscript.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6/22
Y1 - 2023/6/22
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Immunometabolic disease
KW - Mechanism of disease
KW - Ncor1
KW - Nuclear receptor corepressor
U2 - 10.1186/s12933-023-01865-w
DO - 10.1186/s12933-023-01865-w
M3 - Article
C2 - 37349757
AN - SCOPUS:85162736414
SN - 1475-2840
VL - 22
JO - Cardiovascular Diabetology
JF - Cardiovascular Diabetology
M1 - 144
ER -