PPARa and related nuclear receptors in non-alcoholic fatty liver disease

项目概要/摘要 肥胖和 2 型糖尿病的流行增加了相关心脏代谢疾病的患病率 包括血清甘油三酯（TG）升高和非酒精性脂肪肝（NAFLD）。有复活的 对针对肝核受体 PPARα 的药物感兴趣。此类贝特类药物已用于 高甘油三酯血症，并且有新认识认为甘油三酯独立导致动脉粥样硬化性心血管疾病 降低 TG 可降低风险。 Furthermore, PPAR agonists may be among the first drugs 批准用于 NAFLD。 NAFLD 的不良临床结果，如肝硬化肝衰竭、肝细胞癌、 肝相关死亡均与肝纤维化密切相关。我们在 NAFLD 小鼠模型中的初步数据 出人意料地表明 PPARα 缺乏和 PPARα 激动剂治疗均未能改变肝脂肪变性， 但显着影响纤维化（分别增加和减少）。 PPARα 在肝细胞中发挥结合作用 调节DNA并影响脂质代谢关键基因的表达。相关的核受体HNF4α是 不是药物靶点，但调节相似的基因并结合相似的调控 DNA。我们假设相互作用 PPARα和HNF4α在DNA结合中影响肝细胞基因调控，与发病机制和 NAFLD 的治疗。我们的实验探测全基因组核受体结合位点和基因调控， in normal and steatotic livers, basally and in response to drugs.目标 1 定义了 PPARα 的相互依赖性 和 HNF4α 在肝脏基因调控中的作用，使用了其中一种或两种缺陷的小鼠模型。目标 2 扩展了这些研究 在小鼠模型和人类生物样本中，PPARα 和 HNF4α 与 NAFLD 的关系。目标 3 部署强大 遗传学工具来表征 PPARα 和 HNF4α 在序列特异性 DNA 结合中的相互作用。通过比较 近交系小鼠品系中，影响结合基序的自然多态性将揭示选择性和 PPARα 和 HNF4α 常见的 DNA 结合。 In human liver samples, we will test the hypothesis that that non- PPARα/HNF4α 基因组结合位点的编码遗传变异是 TG 人群中某些差异的基础 水平、NAFLD 以及这些药物对 PPARα 激动剂药物的反应。除了这种潜在的临床相关性之外，这些 研究使用创新的基因组和遗传学方法来解决生物学中未解答的关键问题 PPARα，包括其与相关核受体的相互作用。

PROJECT SUMMARY/ABSTRACT The epidemic of obesity and type 2 diabetes has increased prevalence of associated cardiometabolic diseases including elevated serum triglycerides (TGs) and non-alcoholic fatty liver disease (NAFLD). There is resurgent interest in drugs targeting the hepatic nuclear receptor PPARα. Such fibrate drugs are already used in hypertriglyceridemia, and there is new appreciation that TGs independently cause atherosclerotic cardiovascular disease such that lowering TGs reduces risk. Furthermore, PPAR agonists may be among the first drugs approved for NAFLD. Adverse clinical outcomes in NAFLD like cirrhotic liver failure, hepatocellular carcinoma, and liver-related death are all closely linked to hepatic fibrosis. Our preliminary data in a NAFLD mouse model show unexpectedly that PPARα deficiency and PPARα agonist treatment both fail to change hepatic steatosis, but markedly affect fibrosis (increasing and decreasing it, respectively). PPARα functions in hepatocytes to bind regulatory DNA and affect expression of key genes in lipid metabolism. The related nuclear receptor HNF4α is not a drug target, yet regulates similar genes and binds similar regulatory DNA. We hypothesize that the interplay of PPARα and HNF4α in DNA binding affects hepatocyte gene regulation, relevant to the pathogenesis and therapeutics of NAFLD. Our experiments probe genome-wide nuclear receptor binding sites and gene regulation, in normal and steatotic livers, basally and in response to drugs. Aim 1 defines the interdependency of PPARα and HNF4α in liver gene regulation, using mouse models deficient in either or both. Aim 2 extends these studies of PPARα and HNF4α to NAFLD, in both mouse models and human biospecimens. Aim 3 deploys the powerful tools of genetics to characterize PPARα and HNF4α interplay in sequence-specific DNA binding. By comparing inbred mouse strains, natural polymorphisms affecting binding motifs will reveal mechanisms for selective and common DNA binding by PPARα and HNF4α. In human liver samples, we will test the hypothesis that that non- coding genetic variants in PPARα/HNF4α genomic binding sites underlie some differences among people in TG levels, NAFLD, and response of these to PPARα agonist drugs. Beyond this potential clinical relevance, these studies use innovative genomic and genetic approaches to address key unanswered questions in the biology of PPARα, including its interplay with related nuclear receptors.