Hepatic Wnt/LRP6 Regulation of Plasma Lipids

描述(申请人提供)：混合性高脂血症(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血脂紊乱。因此，没有一种单一的治疗药物可以使血浆低密度脂蛋白和甘油三酯完全正常化，或者预防心血管疾病。我们已经确定了Wnt辅助受体LRP6罕见的功能突变，它是早期动脉粥样硬化的基础，以及包括CHL在内的代谢表型。自我们最初发现以来，Wnt蛋白和LRP6拮抗剂的血浆水平和/或功能改变一直与普通人群中高脂血症和早发性CAD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。这些发现表明Wnt信号与高脂血症和早发性动脉粥样硬化有关。为了探讨发病机制，我们建立了人类LRP6R611C(LRP6mut/mut)点突变的小鼠。LRP6mut/mut小鼠在高胆固醇饮食下血浆甘油三酯(TG)和低密度脂蛋白(LDL)胆固醇显著升高，与LDLR/小鼠杂交后显著增加。对这些小鼠的进一步研究发现，肝脏IGF1/IGF1R的表达增强与AKT/mTOR通路的活性增强有关，导致SREBP1和2的激活、脂质合成和ApoB分泌的增加。值得注意的是，全身应用Wn3a后，上述改变恢复正常，高脂血症得到缓解。我们已经设计了几个小鼠模型，并建议研究规范的WNT/�Tenin/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。这些研究为确定治疗混合性高脂血症的新途径和潜在靶点提供了巨大的希望。

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.