Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, New York, USA.
J Clin Invest. 2010 Dec;120(12):4410-4. doi: 10.1172/JCI44213. Epub 2010 Nov 15.
Recent genome-wide association studies have identified a genetic locus at human chromosome 8q24 as having minor alleles associated with lower levels of plasma triglyceride (TG) and LDL cholesterol (LDL-C), higher levels of HDL-C, as well as decreased risk for myocardial infarction. This locus contains only one annotated gene, tribbles homolog 1 (TRIB1), which has not previously been implicated in lipoprotein metabolism. Here we demonstrate a role for Trib1 as a regulator of lipoprotein metabolism in mice. Hepatic-specific overexpression of Trib1 reduced levels of plasma TG and cholesterol by reducing VLDL production; conversely, Trib1-knockout mice showed elevated levels of plasma TG and cholesterol due to increased VLDL production. Hepatic Trib1 expression was inversely associated with the expression of key lipogenic genes and measures of lipogenesis. Thus, we provide functional evidence for what we believe to be a novel gene regulating hepatic lipogenesis and VLDL production in mice that influences plasma lipids and risk for myocardial infarction in humans.
最近的全基因组关联研究已经确定了人类 8q24 染色体上的一个遗传位点，该位点的次要等位基因与血浆甘油三酯 (TG) 和 LDL 胆固醇 (LDL-C) 水平降低、HDL-C 水平升高以及心肌梗死风险降低有关。这个位点只包含一个注释基因，即 tribbles 同源物 1 (TRIB1)，它以前与脂蛋白代谢无关。在这里，我们证明了 Trib1 在调节小鼠脂蛋白代谢中的作用。TRIB1 的肝特异性过表达通过减少 VLDL 的产生降低了血浆 TG 和胆固醇水平；相反，TRIB1 敲除小鼠由于 VLDL 产生增加而表现出血浆 TG 和胆固醇水平升高。肝TRIB1 的表达与关键脂肪生成基因的表达和脂肪生成的测定呈负相关。因此，我们为我们认为在调节小鼠肝脂肪生成和 VLDL 产生中具有新颖作用的基因提供了功能证据，该基因影响人类的血浆脂质和心肌梗死风险。
