Genetics of Cd36 and the hypertension metabolic syndrome

Although genetic mapping of quantitative trait loci (QTL) for complex traits related to hypertension is relatively straightforward, the identification of QTL at the molecular level has proven far more difficult. By combining techniques of gene mapping and gene expression profiling with studies in congenic and transgenic strains, a specific molecular defect in the Cd36 fatty acid transporter has been identified that contributes to the pathogenesis of 2 complex traits in the spontaneously hypertensive rat (SHR), namely, insulin resistance and disordered fatty acid metabolism. After mapping QTL linked to insulin resistance and dyslipidemia to the telomeric region of SHR chromosome 4, gene expression studies were used to identify candidate genes within the target chromosome segment that were differentially expressed in white adipose tissue between SHR congenic strains. This led to the identification of a major mutation in the SHR gene encoding Cd36, a fatty acid transporter involved in the transmembrane transport of long-chain fatty acids. The role for mutant Cd36 in the pathogenesis of insulin resistance and dyslipidemia was confirmed by rescuing the abnormal metabolic phenotypes through transgenic expression of wild-type Cd36 on the SHR background. These findings show that a primary defect in fatty acid transport can promote disordered carbohydrate metabolism in the SHR and show the power of advanced genome technologies for identifying QTL at the molecular level.