期刊
NATURE GENETICS
卷 46, 期 4, 页码 352-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2901
关键词
-
资金
- US National Institutes of Health [HL20948, 1HL092550, DK090066]
- National Center for Advancing Translational Sciences [UL1TR001105]
Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. To elucidate the molecular basis of NAFLD, we performed an exome-wide association study of liver fat content. Three variants were associated with higher liver fat levels at the exome-wide significance level of 3.6 Chi 10(-7): two in PNPLA3, an established locus for NAFLD, and one (encoding p. Glu167Lys) in TM6SF2, a gene of unknown function. The TM6SF2 variant encoding p. Glu167Lys was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and with lower levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides and alkaline phosphatase in 3 independent populations (n > 80,000). When recombinant protein was expressed in cultured hepatocytes, 50% less Glu167Lys TM6SF2 protein was produced relative to wild-type TM6SF2. Adeno-associated virus-mediated short hairpin RNA knockdown of Tm6sf2 in mice increased liver triglyceride content by threefold and decreased very-low-density lipoprotein (VLDL) secretion by 50%. Taken together, these data indicate that TM6SF2 activity is required for normal VLDL secretion and that impaired TM6SF2 function causally contributes to NAFLD.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据