Hepatic Wnt/LRP6 Regulation of Plasma Lipids

描述（由申请人提供）：混合型高脂血症（CHL）是一般人群中最常见的脂质疾病，其遗传病因学和分子机制尚不清楚。因此，没有单一的治疗剂可完全正常化血浆LDL和TG两者，和/或预防心血管疾病。我们已经确定了Wnt辅助受体LRP 6中罕见的功能缺失突变，这些突变是早期动脉粥样硬化和代谢表型（包括CHL）的基础。自从我们最初发现Wnt蛋白和LRP 6拮抗剂的血浆水平和/或功能改变与一般人群中高脂血症和早发性CAD的风险相关。此外，Wnt转录因子TCF 7 L2的常见变异与家族性CHL相关。这些发现涉及Wnt信号在高脂血症和早发性动脉粥样硬化。为了研究疾病机制，产生具有人LRP 6 R611 C（LRP 6 mut/mut）点突变的小鼠。LRP 6 mut/mut小鼠在高胆固醇饮食下表现出显著升高的血浆甘油三酯（TG）和LDL胆固醇，其在与LDLR/小鼠杂交后显著增加。在这些小鼠中的进一步研究显示，肝脏IGF 1/IGF 1 R的表达增强与AKT/mTOR途径的活性增强相关，导致SREBP 1和2活化、脂质合成和ApoB分泌增加。引人注目的是，这些变化正常化并且高脂血症通过全身性Wn 3a施用而得到挽救。我们设计了几种小鼠模型，并建议研究经典Wnt/β tenin/TCF 7 L2及其潜在下游途径IGF 1和mTORC 2在调节脂质合成和ApoB分泌中的作用。这些研究为确定新的途径和开发治疗混合型高脂血症的潜在靶点提供了很大的希望。

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/�tenin/ 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.