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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

LDL-Receptor mRNA Expression in Men Is Downregulated within an Hour of an Acute Fat Load and Is Influenced by Genetic Polymorphism^1–3,

Departments of ⁴ Clinical Immunology and Biochemical Genetics and ⁵ Cardiology, Royal Perth Hospital; Perth, Australia 6000; Schools of ⁶ Surgery and Pathology and ⁷ Medicine and Pharmacology, University of Western Australia, Nedlands, Australia 6009; ⁸ Centre for Clinical Immunology and Biomedical Statistics, Murdoch University and Royal Perth Hospital, Perth, Australia 6000; and ⁹ School of Biomedical Sciences, Curtin University of Technology, Bentley, Australia 6102

^* To whom correspondence should be addressed. E-mail: c.mamotte{at}curtin.edu.au.

Little is known about the immediate effects of dietary fat on the expression of genes involved in cholesterol metabolism in humans. We investigated the effects of a high-fat meal on circulating mononuclear cell messenger RNA (mRNA) for the LDL receptor (LDLR), LDLR-related protein (LRP), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) over 10 h. Selection of 12 C and 7 T homozygotes for the LRP exon 22 C200T polymorphism for the study also enabled us to examine the influence of this polymorphism on postprandial mRNA expression and lipoproteins, of relevance because of LRP's role in postprandial lipoprotein metabolism and association of the polymorphism with coronary artery disease. We found a postprandial decrease in LDLR mRNA abundance relative to the reference ß-actin (BA) mRNA. The decreased LDLR/BA mRNA value was apparent at 1 h (P < 0.005) and decreased to 25% of baseline at 6 h (P < 0.005). The LRP/BA mRNA value was also lower at 6 h (16% decrease, P < 0.05). HMGCR mRNA expression was unchanged. C homozygotes for the C200T polymorphism had higher LDLR/BA values than T homozygotes (P = 0.01) and although plasma LDL cholesterol (LDL-C) concentrations decreased in the postprandial period (P < 0.002), the decrease was less in C than in T homozygotes (P < 0.05). This study constitutes the first observation, to our knowledge, of postprandial changes in LDLR and LRP mRNA expression. It documents immediate effects of a fatty meal on these mRNA as well as an LRP genotype effect on LDLR mRNA and LDL-C.

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