Aitman T J, Glazier A M, Wallace C A, Cooper L D, Norsworthy P J, Wahid F N, Al-Majali K M, Trembling P M, Mann C J, Shoulders C C, Graf D, St Lezin E, Kurtz T W, Kren V, Pravenec M, Ibrahimi A, Abumrad N A, Stanton L W, Scott J
MRC Clinical Sciences Centre, and Division of National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Nat Genet. 1999 Jan;21(1):76-83. doi: 10.1038/5013.
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.
人类胰岛素抵抗综合征、2型糖尿病、肥胖症、混合性高脂血症和原发性高血压都是复杂的疾病，其遗传基础尚不清楚。自发性高血压大鼠（SHR）存在胰岛素抵抗，是这些人类综合征的模型。葡萄糖和脂肪酸代谢缺陷、高甘油三酯血症和高血压的SHR缺陷数量性状基因座（QTL）定位于大鼠4号染色体上的一个单一基因座。在这里，我们结合使用cDNA微阵列、近交系定位和辐射杂种（RH）定位，在与这些QTL连锁的峰值处鉴定出一个有缺陷的SHR基因Cd36（也称为Fat，因为它编码脂肪酸转运蛋白）。SHR Cd36 cDNA包含多个序列变体，这是由一个重复的祖先基因的不等基因组重组引起的。在SHR脂肪细胞质膜中检测不到编码的蛋白质产物。过表达Cd36的转基因小鼠血脂降低。我们得出结论，Cd36缺乏是SHR胰岛素抵抗、脂肪酸代谢缺陷和高甘油三酯血症的基础，可能在人类胰岛素抵抗综合征的发病机制中起重要作用。
