Study the role of oxysterol sulfates in NAFLD development

项目摘要 肝脏在维持脂质平衡中起着关键作用。脂肪在肝脏中的积聚 不喝酒会导致非酒精性脂肪性肝病(NAFLD)。NAFLD光谱范围从 单纯性非酒精性脂肪肝(脂肪变性)到脂肪性肝炎(NASH)和肝硬变。胰岛素抵抗 代谢紊乱和随后的炎症是发展的主要发病机制。 疾病，但机制的细节还没有完全了解。大多数研究都集中在 游离脂肪酸介导的脂毒性作用。然而，事实表明，存在普遍的监管失调。 非酒精性脂肪性肝病的脂肪代谢，具体地说，在胆固醇代谢方面存在重大干扰。这个 这种扰动可能导致肝病的潜在机制尚不清楚。这一差距在 这一领域是理解胆固醇代谢产物在糖尿病发病机制中作用的主要障碍。 NASH和利用这些信息来开发治疗NAFLD的新疗法。 我们最近在正常人中发现了新的调节胆固醇代谢产物，25HC3S和25HCDS 人体血浆和肝组织。给予代谢物或增加其表达 羟基固醇磺基转移酶(SULT2B1b，合成这些代谢物的关键酶) 减少血清和肝脏组织中的脂肪堆积。这项建议的重点是 NAFLD发病过程中的代谢物。假设：基于我们强劲的初步数据，我们 建议减少SULT2B1b活性，从而减少25HC3S/25HCDS促进 肝脏脂肪变性：(1)未能抑制促脂肪转录因子类固醇反应元件 结合蛋白(SREBPs)和(2)降低过氧化物酶体增殖物的表达和活性- 通过表观基因组调控激活受体-(PPAR)，激活组蛋白脱乙酰酶(SirT1)。我们将测试 这一假说的具体目的如下：1)阐明生物化学机制 胆固醇代谢产物调节脂质代谢和炎症反应。2)探索 SULT2B1b在体外游离脂肪酸诱导和体内高脂饮食诱导的NALFD形成中的作用 模特们。3)测试胆固醇代谢产物预防/逆转肝脏脂质堆积的潜力 在NAFLD动物模型中。这项提议的总体目标是了解分子机制。 硫酸氧合甾醇参与肝细胞脂代谢的协调调节 并探讨其作为治疗非酒精性脂肪肝的潜在临床应用价值。

Project Summary The liver plays a pivotal role in the maintenance of lipid homeostasis. Accumulation of lipids in the liver with no alcoholic consumption leads to nonalcoholic fatty liver diseases (NAFLD). NAFLD spectrum ranges from a simple nonalcoholic fatty liver (steatosis) to steatohepatitis (NASH) and cirrhosis. Insulin resistant metabolic disorder and subsequent inflammation are the major pathogenesis for development of the diseases, but the details of the mechanisms are not fully understood. Most studies have focused on the role of free fatty acid-mediated lipotoxicity. It has however been shown that there is widespread dysregulation of lipid metabolism in NAFLD and, specifically, there are major perturbations in cholesterol metabolism. The potential mechanisms by which such perturbations may lead to liver diseases remain unknown. This gap in the field is a major barrier towards understanding the role of cholesterol metabolites in the pathogenesis of NASH and leveraging this information to develop novel therapies for NAFLD. We recently identified novel regulatory cholesterol metabolites, 25HC3S and 25HCDS, in normal human plasma and liver tissues. Administration of the metabolites or increase in expression of hydroxysterol sulfotransferase (SULT2B1b, the key enzyme for the synthesis of these metabolites) decreases lipid accumulation in serum and liver tissues. This proposal focuses on the role of the metabolites in the development of NAFLD. Hypothesis: Based on our strong preliminary data, we propose that decreases in SULT2B1b activity with consequent decreases in 25HC3S/25HCDS promote hepatic steatosis by (1) fail to inhibit the pro-lipogenic transcriptional factor sterol response element binding proteins (SREBPs) and (2) decrease expression and activity of the peroxisome proliferator- activated receptor- (PPAR) via epigenomic regulation, activating histone deacetylase (SirT1). We will test the hypothesis by the following specific aims: 1) To elucidate the biochemical mechanism by which the cholesterol metabolites regulate lipid metabolism and inflammatory responses. 2) To explore the role of SULT2B1b in development of NALFD in vitro in free fatty acid-induced and in vivo high fat diet-induced NALFD models. 3) To test the potential of the cholesterol metabolites to prevent/reverse hepatic lipid accumulation in NAFLD animal models. The overall goal of this proposal is to understand the molecular mechanisms of oxysterol sulfation involved in the coordinate regulation of hepatocyte lipid metabolism and inflammatory responses, and to explore its potential clinical utility as a treatment for NAFLD.