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461 DOWN-REGULATION OF HEPATIC HIGH-DENSITY LIPOPROTEIN RECEPTOR PROTEINS IN HEREDITARY OBESITY.
  1. H. Moradi,
  2. N. D. Vaziri
  1. Division of Nephrology and Hypertension, University of California, Irvine, CA

Abstract

Obesity and metabolic syndrome have emerged as the major risk factors for atherosclerotic cardiovascular diseases, which are the main cause of morbidity and mortality worldwide. HDL plays a key role in prevention of atherosclerosis by facilitating the transport of surplus cholesterol from the extrahepatic tissues for disposal in the liver. Scavenger receptor class B type I (SR-BI) serves as a docking platform for unloading of HDL cholesterol in the liver, which is followed by the release of the unloaded HDL for recycling. Recently, the beta chain of mitochondrial ATP synthase was shown to serve as the receptor for internalization and degradation of the HDL particles by the liver. On the other hand, ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of phospholipids and free cholesterol from the liver for uptake by the lipid-poor apoA-I, an event which is critical in formation of nascent HDL. Thus, together these proteins play a crucial role in HDL metabolism and reverse cholesterol transport. The genetically obese Zucker rats have been frequently used as a model to study obesity-induced dyslipidemia and metabolic syndrome. Homozygous (fa/fa) Zucker rats exhibit hyperphagia, which leads to obesity, insulin resistance, hyperlipidemia, renal disease, and tissue lipid accumulation. Given the impact of obesity and metabolic syndrome on plasma lipid and lipoproteins, we examined hepatic expression of the above HDL-regulatory receptors in the liver of lean and obese Zucker rats using Western blot analysis. At 22 weeks of age, the obese Zucker rats exhibited moderate hypercholesterolemia, severe hypertriglyceridemia, and a marked increase in body weight as compared to the lean Zucker rats. Expressions of both SR-BI and β chain ATP synthase were decreased significantly in the obese Zucker rats when compared to those found in their lean counterparts. However, hepatic ABCA1 protein expression in the obese rats was comparable with that found in the lean animals. In conclusion, hyperlipidemia in the obese Zucker rats is associated with hepatic SRB-1 and beta chain of ATP synthase deficiencies. These abnormalities can contribute to dyslipidemia and defective reverse cholesterol transport in this model of metabolic syndrome.

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