Southwest National Primate Research Center, Southwest Foundation for Biomedical Research , San Antonio, TX, USA.
J Lipid Res. 2010 Oct;51(10):2922-8. doi: 10.1194/jlr.M005553. Epub 2010 May 20.
High-responding opossums are susceptible to developing hypercholesterolemia on a high-cholesterol diet, but low-responding opossums are resistant. The observation of low biliary cholesterol and low biliary phospholipids in high responders suggested that the ABCB4 gene affects response to dietary cholesterol. Two missense mutations (Arg29Gly and Ile235Leu) were found in the ABCB4 gene of high responders. High responders (ATHH strain) were bred with low responders (ATHE or ATHL strain) to produce F1 and F2 progeny in two different genetic crosses (KUSH6 and JCX) to determine the effect of ABCB4 allelic variants on plasma cholesterol concentrations after a dietary challenge. Pedigree-based genetic association analyses consistently implicated a variant in ABCB4 or a closely linked locus as a major, but not the sole, genetic contributor to variation in the plasma cholesterol response to dietary cholesterol. High responders, but not low responders, developed liver injury as indicated by elevated plasma biomarkers of liver function, probably reflecting damage to the canalicular membrane by bile salts because of impaired phospholipid secretion. Our results implicate ABCB4 as a major determinant of diet-induced hypercholesterolemia in high-responding opossums and suggest that other genes interact with ABCB4 to regulate lipemic response to dietary cholesterol.
高反应的负鼠在高胆固醇饮食下容易发生高胆固醇血症，但低反应的负鼠则具有抗性。高反应者胆汁胆固醇和胆汁磷脂较低的观察结果表明，ABCB4 基因影响对膳食胆固醇的反应。在高反应者的 ABCB4 基因中发现了两种错义突变（Arg29Gly 和 Ile235Leu）。高反应者（ATHH 品系）与低反应者（ATHE 或 ATHL 品系）交配，在两种不同的遗传杂交（KUSH6 和 JCX）中产生 F1 和 F2 后代，以确定 ABCB4 等位基因变体对膳食胆固醇挑战后血浆胆固醇浓度的影响。基于家系的遗传关联分析一致表明，ABCB4 或紧密连锁的基因座中的一个变体是对膳食胆固醇引起的血浆胆固醇反应变异的主要遗传因素，但不是唯一因素。高反应者而非低反应者发生了肝损伤，表现为血浆肝功能生物标志物升高，可能反映了由于磷脂分泌受损而导致的胆汁盐对胆小管膜的损伤。我们的研究结果表明，ABCB4 是高反应负鼠饮食诱导性高胆固醇血症的主要决定因素，并表明其他基因与 ABCB4 相互作用，以调节对膳食胆固醇的脂血症反应。
