TY - JOUR
T1 - Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats
AU - Aitman, Timothy J.
AU - Glazier, Anne M.
AU - Wallace, Caroline A.
AU - Cooper, Lisa D.
AU - Norsworthy, Penny J.
AU - Wahid, Faisal N.
AU - Al-Majali, Khulood M.
AU - Trembling, Paul M.
AU - Mann, Christopher J.
AU - Shoulders, Carol C.
AU - Graf, Daniel
AU - St. Lezin, Elizabeth
AU - Kurtz, Theodore W.
AU - Kren, Vladimir
AU - Pravenec, Michal
AU - Ibrahimi, Azeddine
AU - Abumrad, Nada A.
AU - Stanton, Lawrence W.
AU - Scott, James
PY - 1999/1
Y1 - 1999/1
N2 - The human insulin-resistance syndromes, type 2 diabetes, obesity, combined hyperlipidaemia and essential hypertension, are complex disorders whose genetic basis is unknown. The spontaneously hypertensive rat (SHR) is insulin resistant and a model of these human syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a single locus on rat chromosome 4. Here we combine use of cDNA microarrays, congenic mapping and radiation hybrid (RH) mapping to identify a defective SHR gene, Cd36 (also known as Fat, as it encodes fatty acid translocase), at the peak of linkage to these QTLs. SHR Cd36 cDNA contains multiple sequence variants, caused by unequal genomic recombination of a duplicated ancestral gene. The encoded protein product is undetectable in SHR adipocyte plasma membrane. Transgenic mice overexpressing Cd36 have reduced blood lipids. We conclude that Cd36 deficiency underlies insulin resistance, defective fatty acid metabolism and hypertriglyceridaemia in SHR and may be important in the pathogenesis of human insulin-resistance syndromes.
AB - The human insulin-resistance syndromes, type 2 diabetes, obesity, combined hyperlipidaemia and essential hypertension, are complex disorders whose genetic basis is unknown. The spontaneously hypertensive rat (SHR) is insulin resistant and a model of these human syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a single locus on rat chromosome 4. Here we combine use of cDNA microarrays, congenic mapping and radiation hybrid (RH) mapping to identify a defective SHR gene, Cd36 (also known as Fat, as it encodes fatty acid translocase), at the peak of linkage to these QTLs. SHR Cd36 cDNA contains multiple sequence variants, caused by unequal genomic recombination of a duplicated ancestral gene. The encoded protein product is undetectable in SHR adipocyte plasma membrane. Transgenic mice overexpressing Cd36 have reduced blood lipids. We conclude that Cd36 deficiency underlies insulin resistance, defective fatty acid metabolism and hypertriglyceridaemia in SHR and may be important in the pathogenesis of human insulin-resistance syndromes.
UR - https://www.scopus.com/pages/publications/0032958470
U2 - 10.1038/5013
DO - 10.1038/5013
M3 - Article
C2 - 9916795
AN - SCOPUS:0032958470
SN - 1061-4036
VL - 21
SP - 76
EP - 83
JO - Nature Genetics
JF - Nature Genetics
IS - 1
ER -