Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Increased Hepatic Lipogenesis Elevates Liver Cholesterol Content

  • Berger, Jean-Mathieu (Departments of Internal Medicine and Molecular Genetics, University of Texas Southwestern Medical Center) ;
  • Moon, Young-Ah (Department of Molecular Medicine, Inha University College of Medicine)
  • Received : 2020.07.07
  • Accepted : 2021.02.07
  • Published : 2021.02.28
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Abstract

Cardiovascular diseases (CVDs) are the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) and dyslipidemia is considered at least partially responsible for the increased CVD risk in NAFLD patients. The aim of the present study is to understand how hepatic de novo lipogenesis influences hepatic cholesterol content as well as its effects on the plasma lipid levels. Hepatic lipogenesis was induced in mice by feeding a fat-free/high-sucrose (FF/HS) diet and the metabolic pathways associated with cholesterol were then analyzed. Both liver triglyceride and cholesterol contents were significantly increased in mice fed an FF/HS diet. Activation of fatty acid synthesis driven by the activation of sterol regulatory element binding protein (SREBP)-1c resulted in the increased liver triglycerides. The augmented cholesterol content in the liver could not be explained by an increased cholesterol synthesis, which was decreased by the FF/HS diet. HMG-CoA reductase protein level was decreased in mice fed an FF/HS diet. We found that the liver retained more cholesterol through a reduced excretion of bile acids, a reduced fecal cholesterol excretion, and an increased cholesterol uptake from plasma lipoproteins. Very low-density lipoproteintriglyceride and -cholesterol secretion were increased in mice fed an FF/HS diet, which led to hypertriglyceridemia and hypercholesterolemia in Ldlr-/- mice, a model that exhibits a more human like lipoprotein profile. These findings suggest that dietary cholesterol intake and cholesterol synthesis rates cannot only explain the hypercholesterolemia associated with NAFLD, and that the control of fatty acid synthesis should be considered for the management of dyslipidemia.

Keywords

Acknowledgement

This work was supported by grants from the National Research Foundation of Korea funded by the Korean government (2018R1A2B6007576), the National Institutes of Health (HL-20948), and the Leducq Foundation (5200829301). The authors thank Sijeong Bae (Department of Molecular Medicine, Inha University College of Medicine) Angel Loza Valdes, Ajit Kumar Koduri, Tuyet Dang, Judith Sanchez, Norma Anderson, and Lisa Beatty (Department of Molecular Genetics, UT Southwestern Medical Center), and Abhijit Bugde (the Live Cell Imaging Core Facility, UT Southwestern Medical Center) for their technical assistance. The authors also thank Dr. Youngah Jo for providing the anti-HMG CoA-R antibody and Dr. Jay Horton for scientific advice.

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