Identification of Defective CD36 as a Quantitative Trait Locus for Cardiovascular Risk Factor Clustering in the Spontaneously Hypertensive Rat

It was demonstrated that a gene or genes responsible for a whole spectrum of cardiovascular risk factors map to a limited segment of the centromeric region of rat chromosome 4. Recently, a spontaneous deletion in the gene for Cd36 that encodes a fatty acid transporter and is located directly at the peak of QTL linkages on chromosome 4 has been indirectly linked to the transmission of insulin resistance, defective fatty acid metabolism, and increased blood pressure. To directly test whether mutant Cd36 is a QTL that promotes clustering of multiple cardiovascular risk factors in the Spontaneously Hypertensive Rat (SHR), transgenic lines were derived that carry a wild type Cd36 transgene on the genetic background of the SHR strain harboring a deletion variant of Cd36. It was found that in SHR harboring the deletion variant of Cd36, transgenic expression of wild type Cd36 in modest amounts ameliorated defects in fatty acid metabolism, glucose tolerance, and insulin stimulated glucose uptake in muscle and fat tissue, however, exerted little or no effect on blood pressure. In conclusion, the current studies provided definitive evidence that mutant Cd36 is a QTL with major effects on fatty acid metabolism, insulin action, and glucose tolerance but have no effects on spontaneous hypertension in the SHR/NIH strains.