Hepatic Wnt/LRP6 Regulation of Plasma Lipids

描述（由申请人提供）：联合高脂血症（CHL）的遗传病因和分子机制尚不清楚，CHL是普通人群中最常见的脂质疾病。因此，目前还没有单一的治疗药物可以使血浆LDL和TG完全正常化，并预防心血管疾病。我们已经发现了罕见的Wnt共受体LRP6功能突变缺失，这是早期动脉粥样硬化和代谢表型（包括CHL）的基础。自我们最初发现Wnt蛋白和LRP6拮抗剂的血浆水平和（或）功能改变以来，在普通人群中，Wnt蛋白和LRP6拮抗剂与高脂血症和早发性冠心病的风险有关。此外，Wnt转录因子TCF7L2的常见变异与家族性CHL有关。这些发现提示Wnt信号与高脂血症和早发性动脉粥样硬化有关。为了研究致病机制，我们制造了携带人类LRP6R611C （LRP6mut/mut）点突变的小鼠。LRP6mut/mut小鼠在高胆固醇饮食条件下血浆甘油三酯（TG）和低密度脂蛋白胆固醇显著升高，与LDLR/小鼠杂交后显著升高。在这些小鼠中进一步的研究发现肝脏IGF1/IGF1R的表达增强与AKT/mTOR通路活性增强相关，导致SREBP1和2活化、脂质合成和ApoB分泌增加。引人注目的是，这些变化正常化，高脂血症被全身给药Wn3a挽救。我们设计了几种小鼠模型，并提出研究典型的Wnt/ß-catenin/ TCF7L2及其潜在的下游通路IGF1和mTORC2在调节脂质合成和ApoB分泌中的作用。这些研究对于确定新的途径和潜在的靶点来开发治疗合并高脂血症具有很大的希望。

DESCRIPTION (provided by applicant): The genetic etiology and the molecular mechanisms of combined hyperlipidemia (CHL), the most common lipid disorder of the general population is not understood. Accordingly, no single therapeutic agent is available that completely normalizes both plasma LDL and TG, and or prevent cardiovascular disease. We have identified rare loss of function mutations in Wnt coreceptor LRP6 that underlie early atherosclerosis, and metabolic phenotypes including CHL. Since our initial discovery altered plasma levels and or functions of Wnt proteins and LRP6 antagonists have been associated with risk of hyperlipidemia and early onset CAD in the general population. In addition, common variants in Wnt transcription factor TCF7L2 have been associated with familial CHL. These findings have implicated Wnt signaling in hyperlipidemia and early onset atherosclerosis. To investigate disease mechanisms, mice with the human LRP6R611C (LRP6mut/mut) point mutation were generated. LRP6mut/mut mice exhibit significantly elevated plasma triglycerides (TG) and LDL cholesterols on high cholesterol diet, which dramatically increases after they are crossbred onto LDLR/ mice. Further studies in these mice revealed enhanced expression of liver IGF1/IGF1R associated with augmented activities of AKT/mTOR pathways, leading to increased SREBP1 and 2 activation, lipid synthesis and ApoB secretion. Strikingly, these changes normalized and hyperlipidemia was rescued by systemic Wn3a administration. We have devised several mouse models and propose to study the role of canonical Wnt/ß-catenin/ TCF7L2, and their potential downstream pathways IGF1 and mTORC2 in regulation of lipid synthesis and ApoB secretion. These studies hold great promise for identifying novel pathways and potential targets for development of therapeutics against combined hyperlipidemia.