Use of rat genomics for investigating the metabolic syndrome.
The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and accompanying metabolic disturbances. In this model, the use of whole genome sequencing and gene expression profiling techniques, linkage and correlation analyses in recombinant inbred strains, and in vitro and in vivo functional studies in congenic and transgenic lines has recently enabled molecular identification of quantitative trait loci (QTLs) relevant to the metabolic syndrome: (1) a deletion variant in Cd36 (fatty acid translocase) responsible for QTLs on chromosome 4 associated with dyslipidemia, insulin resistance and hypertension, (2) mutated Srebf1 (sterol regulatory element binding factor 1) as a QTL on chromosome 10 influencing dietary-induced changes in hepatic cholesterol levels, and (3) Ogn (osteoglycin) as a QTL on chromosome 17 associated with left ventricular hypertrophy. In addition, selective replacement of the mitochondrial genome of the SHR with the mitochondrial genome of the Brown Norway rat influenced several major metabolic risk factors for type 2 diabetes and provided evidence that spontaneous variation in the mitochondrial genome per se can promote systemic metabolic disturbances relevant to the pathogenesis of metabolic syndrome. Owing to recent progress in the development of rat genomic resources, the pace of QTL identification and discovery of new disease mechanisms can be expected to accelerate in the near future.
Pravenec
Michal
M
Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D023281:Genomics / Q000379:methods*; D024821:Metabolic Syndrome / Q000235:genetics*; D040641:Quantitative Trait Loci; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics*; D011919:Rats, Inbred Strains / Q000235:genetics