Hepatocyte Nuclear Factor 4alpha and Lipid Homeostasis

描述（由申请人提供）：核受体是配体激活的转录因子，在人类和哺乳动物生理学中发挥重要的调节作用。我们有兴趣了解核受体在控制脂质稳态中的作用。我们的长期目标是阐明核受体控制脂质稳态的调节机制，并确定高脂血症和冠心病的潜在治疗靶点。肝细胞核因子4（HNF 4）是核受体超家族成员，在调节胆汁酸、脂质和葡萄糖稳态中发挥重要作用。人类HNF4的功能缺失突变与以常染色体显性遗传和早发性糖尿病为特征的年轻人成熟型糖尿病1（MODY1）相关。此外，人HNF4的功能丧失突变也会导致脂质稳态紊乱，导致血浆甘油三酯和胆固醇水平降低。然而，HNF4缺乏的降血脂作用的机制仍有待确定。此外，HNF4缺乏在动脉粥样硬化中的作用尚未确定。我们推测HNF4缺乏通过抑制胆固醇代谢的多个途径导致低胆固醇血症，并防止动脉粥样硬化的发展。我们将使用肝Hnf4缺乏的小鼠，结合生物化学、分子和细胞方法来确定肝Hnf4缺乏在胆固醇从头合成、VLDL分泌、HDL生物合成、胆固醇逆向转运和预防饮食诱导的高胆固醇血症和动脉粥样硬化中的作用。实现这一建议中的具体目标将为MODY1患者的脂质紊乱机制提供重要的见解，并将帮助我们确定肝HNF4是否是治疗高胆固醇血症和冠心病的靶点。 公共卫生相关性：动脉粥样硬化是冠心病最常见的原因。完成拟议的研究将提供重要的见解的机制，潜在的脂质紊乱的MODY1患者，并将帮助我们确定是否肝HNF4？是高胆固醇血症和动脉粥样硬化的治疗靶点。因此，本申请中提出的研究与心血管疾病和人类健康高度相关。

DESCRIPTION (provided by the applicant): Nuclear receptors are ligand-activated transcription factors that play important regulatory roles in human and mammalian physiology. We are interested in understanding the role of nuclear receptors in controlling lipid homeostasis. Our long-term goal is to elucidate the regulatory mechanisms controlling lipid homeostasis by nuclear receptors and to identify potential therapeutic targets for hyperlipidemia and coronary heart disease. Hepatocyte nuclear factor 4 is a member of the nuclear receptor superfamily and (HNF4 plays an important regulatory roles in bile acid, lipid and glucose homeostasis. Loss-of-function mutations in human HNF4 are associated with maturity-onset diabetes of the young 1 (MODY1), characterized by autosomal dominant inheritance and early onset diabetes. In addition, loss-of-function mutations in human HNF4 also cause disorders in lipid homeostasis, resulting in a reduction in plasma triglyceride and cholesterol levels. However, the mechanism underlying the hypolipidemic effect of HNF4 deficiency remains to be determined. In addition, the role of HNF4 deficiency in atherosclerosis has not been established. We hypothesize that HNF4 deficiency results in hypocholesterolemia via inhibiting multiple pathways of cholesterol metabolism and protects against the development of atherosclerosis. We will use mice deficient in hepatic Hnf4 together with biochemical, molecular and cellular approaches to determine the role of hepatic Hnf4 deficiency in de novo cholesterol synthesis, VLDL secretion, HDL biogenesis, reverse cholesterol transport and in protection against diet-induced hypercholesterolemia and atherosclerosis. Accomplishing the specific aims in this proposal will provide important insights into the mechanisms underlying lipid disorders in MODY1 patients, and will help us determine whether hepatic HNF4 is a target for treatment of hypercholesterolemia and coronary heart disease. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the most common cause for coronary heart disease. Completion of the proposed studies will provide important insights into the mechanism underlying lipid disorders in MODY1 patients and will help us determine whether hepatic HNF4? is a therapeutic target for hypercholesterolemia and atherosclerosis. Thus, the studies proposed in this application are highly relevant to cardiovascular disease and human health.