Molecular mechanisms underlying the genetic association between PPP1R3B and hepatic steatosis

项目总结 非酒精性脂肪性肝病(NAFLD)是一个影响数百万美国人的重大公共卫生问题， 随着全球肥胖率的上升，这一问题的患病率正在上升。尖端的人类遗传方法已经 确定了与肝脏脂肪相关的自然人类遗传变异。其中，与两个基因有关： PNPLA3和PPP1R3B已在多项研究中复制。我们开发了独特的新型鼠标 帮助我们了解增加的PPP1R3B如何预防脂肪肝的模型。PPP1R3B编码一个 已知的调节肝糖原的蛋白质，但仅通过基因联系与肝脏脂肪有关： 换句话说，PPP1R3B在肝脏脂肪代谢中的作用尚不清楚。 有趣的是，PPP1R3B基因还与多种与人类代谢健康相关的性状有关， 包括空腹胰岛素和血糖、血浆乳酸、碱性磷酸酶和血浆胆固醇(总低密度脂蛋白 和高密度脂蛋白胆固醇)。所有这些关联信号都从PPP1R3B基因的末端很远地映射到一个 功能未知的长非编码RNA(LncRNA)，LOC157273。尽管有相当大的物理距离， 研究发现，基因变异与肝脏PPP1R3B RNA的增加有关。次要等位基因(出现在 约9%的欧洲人)与肝脏PPP1R3B mRNA表达增加和肝脏和 血浆脂类。我们在小鼠身上的初步数据强烈表明，PPP1R3B是肝脏特异的致病基因 Ppp1R3B基因敲除小鼠(Ppp1r3bΔHep)肝脏和血浆脂质升高，而 肝脏中Ppp1r3b水平降低肝脏和血脂。我们建议阐明以下机制： 肝脏PPP1R3B影响肝脏脂肪和血浆胆固醇，并确定自然变异体如何 增加PPP1R3B基因的表达。 好了！

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. !