Molecular mechanisms underlying the genetic association between PPP1R3B and hepatic steatosis

项目摘要 非酒精性脂肪肝（NAFLD）是影响数百万美国人的主要公共卫生问题， 随着全球肥胖症的增加，这种疾病的发病率也在增加。最先进的人类遗传学方法 发现了与肝脏脂肪相关的天然人类遗传变异。其中，与两个基因的关联： PNPLA3和PPP1R3B已在多项研究中重复。我们开发了独特的新鼠标 模型，以帮助我们了解PPP1R3B增加如何防止脂肪肝。PPP1R3B编码一个 已知调节肝糖原的蛋白质，但仅通过遗传关联与肝脏脂肪相关： 换句话说，PPP1R3B在肝脏脂肪代谢中的作用是未知的。 有趣的是，PPP1R3B也与人类代谢健康相关的多种性状遗传相关， 包括空腹胰岛素和葡萄糖、血浆乳酸、碱性磷酸酶和血浆胆固醇（总LDL 和HDL胆固醇）。所有这些关联信号都映射到距离PPP1R3B基因末端相当远的位置， 功能未知的长链非编码RNA（lncRNA），LOC157273。尽管物理距离很远， 发现遗传变异与肝脏PPP1R3B RNA增加相关。次要等位基因（发生在 约9%的欧洲人）与肝脏PPP1R3B mRNA表达增加和肝脏和 血浆脂质我们在小鼠中的初步数据强烈表明PPP1R3B是致病基因：肝脏特异性 PPP1R3B基因敲除小鼠（Ppp1r3bΔhep）的肝脏和血浆脂质增加， 肝脏中Ppp1r3b水平降低肝脏和血浆脂质。我们建议阐明的机制， 肝脏PPP1R3B影响肝脏脂肪和血浆胆固醇，并确定天然变体如何影响肝脏脂肪和血浆胆固醇。 增加PPP1R3B基因的表达。 !

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is a major public health issue that affects millions of Americans, and that is increasing in prevalence with the global rise in obesity. Cutting edge human genetic approaches have identified natural human genetic variants associated with liver fat. Of these, associations with two genes: PNPLA3, and PPP1R3B, have been replicated in multiple studies. We have developed unique new mouse models to help us understand how increased PPP1R3B protects against fatty liver. PPP1R3B encodes a protein known to regulate liver glycogen, but which has only been connected to liver fat by genetic association: in other words, the role of PPP1R3B in liver fat metabolism is unknown. Interestingly, PPP1R3B is also genetically associated with multiple traits relevant to human metabolic health, including fasting insulin and glucose, plasma lactate, alkaline phosphatase, and plasma cholesterol (total, LDL and HDL cholesterol). All of these association signals map quite far from the end of the PPP1R3B gene, to a long non-coding RNA (lncRNA) of unknown function, LOC157273. Despite the considerable physical distance, genetic variants were found to correlate with increased liver PPP1R3B RNA. The minor allele (occurring in ~9% of Europeans) is associated with increased hepatic PPP1R3B mRNA expression and reduced liver and plasma lipids. Our preliminary data in mice strongly suggest that PPP1R3B is the causal gene: liver-specific PPP1R3B knockout mice (Ppp1r3bΔhep) have increased hepatic and plasma lipids, whereas increasing Ppp1r3b levels in liver reduces hepatic and plasma lipids. We propose to elucidate the mechanisms by which hepatic PPP1R3B influences hepatic fat and plasma cholesterol, and to determine how the natural variants increase expression of the PPP1R3B gene. !