Study the role of oxysterol sulfates in NAFLD development

研究硫酸氧固醇在 NAFLD 发展中的作用

• 批准号: 10265329
• 负责人: SHUNLIN REN
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265329
• 关键词: Animal Disease Models; Binding Proteins; Biochemical; Biological Markers; Cell Nucleus; Cholesterol; Cholesterol Homeostasis; Cirrhosis; Clinical; Consumption; Data; Development; Diagnosis; Disease; Enzymes; Epigenetic Process; Fatty Liver; Genes; Glycols; Goals; Health; Hepatic; Hepatocyte; High Fat Diet; Histone Deacetylase; Homeostasis; Human; In Vitro; Inflammation; Inflammatory Response; Insulin Resistance; Lead; Ligands; Lipids; Liver; Liver diseases; Maintenance; Mediating; Metabolic Diseases; Metabolic Pathway; Methods; Mission; Modeling; Molecular; Monitor; Morbidity - disease rate; Nonesterified Fatty Acids; Nuclear; Pathogenesis; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Physiological; Plasma; Play; Recovery; Regulation; Regulatory Pathway; Research Personnel; Response Elements; Role; Route; SIRT1 gene; SULT2B1; Serum; Small Interfering RNA; Steatohepatitis; Sterols; Sulfate; Systems Biology; Testing; Therapeutic; Tissues; Transgenic Mice; Translational Research; United States; Veterans; base; epigenetic regulation; epigenomics; experimental study; in vivo; knock-down; lipid metabolism; metabolomics; mortality; non-alcoholic fatty liver; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; novel therapeutics; overexpression; population health; preclinical development; prevent; problem drinker; programs; recombinant adenovirus; sulfotransferase; transcription factor

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.

项目摘要 肝脏在维持脂质稳态中起着关键作用。脂质在肝脏中蓄积， 不饮酒会导致非酒精性脂肪性肝病（NAFLD）。NAFLD谱范围从 从单纯非酒精性脂肪肝（脂肪变性）到脂肪性肝炎（NASH）和肝硬化。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，但机制的细节尚未完全了解。大多数研究都集中在 游离脂肪酸介导的脂毒性的作用。然而，研究表明， NAFLD中脂质代谢的变化，特别是胆固醇代谢存在重大扰动。的 这种扰动可能导致肝脏疾病的潜在机制仍然未知。中的这一空白 这一领域是理解胆固醇代谢物在胆固醇血症发病机制中作用的主要障碍。 NASH和利用这些信息开发NAFLD的新疗法。 我们最近发现了新的调节胆固醇代谢物，25 HC 3S和25 HCDS，在正常人中， 人血浆和肝组织。代谢物给药或 羟基甾醇磺基转移酶（SULT 2B 1b，合成这些代谢物的关键酶） 减少血清和肝组织中的脂质积累。本建议侧重于 代谢物在NAFLD的发展中的作用。假设：基于我们强大的初步数据，我们 建议SULT 2B 1b活性的降低以及随之而来的25 HC 3S/25 HCDS的降低促进 肝脂肪变性通过（1）未能抑制促脂肪生成转录因子固醇反应元件 结合蛋白（SREBP）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-β（PPAR β），激活组蛋白脱乙酰酶（SirT 1）。我们将测试 通过以下具体目标的假设：1）阐明的生化机制， 胆固醇代谢物调节脂质代谢和炎症反应。2)探讨的作用 SULT 2B 1b在游离脂肪酸诱导的体外NALFD和体内高脂饮食诱导的NALFD中的发展 模型3)检测胆固醇代谢产物预防/逆转肝脏脂质蓄积的潜力 在NAFLD动物模型中。这项提案的总体目标是了解分子机制 参与肝细胞脂质代谢的协调调节， 炎症反应，并探索其作为NAFLD治疗的潜在临床效用。