Regulation of SREBP-1 Processing Lipogenesis by LPCAT

LPCAT 对 SREBP-1 脂肪生成过程的调节

• 批准号: 9330678
• 负责人: Bo Wang
• 金额: $ 4.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330678
• 关键词: ADD-1 protein; Acyltransferase; Affect; Agonist; Anabolism; Biological; Biological Assay; Carbohydrates; Cells; Cytosol; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Dyslipidemias; Enzymes; Fasting; Fatty Acids; Fatty Liver; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Golgi Apparatus; Healthcare; Heart Diseases; Hepatic; Hepatocyte; Histology; Hormonal; Human; Impairment; In Vitro; Insulin; Knock-out; Knockout Mice; Lecithin; Ligands; Lipids; Liver; Liver Failure; Liver X Receptor; Lysophosphatidylcholines; Malignant Neoplasms; Measures; Mediating; Membrane; Membrane Fluidity; Messenger RNA; Metabolic; Metabolic Diseases; Molecular; Mus; Nuclear; Nuclear Receptors; Nutritional; Obese Mice; Obesity; Organelles; Pathologic; Pathway interactions; Phosphatidylethanolamine; Phospholipids; Physiological; Physiological Processes; Polyunsaturated Fatty Acids; Post-Translational Protein Processing; Prevalence; Process; Publishing; Regulation; Research; Research Project Grants; Role; SRE-1 binding protein; SRE-2 binding protein; Signal Transduction; Specificity; Sterols; Testing; Therapeutic; Transcriptional Activation; Transport Process; Triglycerides; Unsaturated Fatty Acids; Very low density lipoprotein; Vesicle; Western World; Work; base; effective therapy; fatty acid biosynthesis; human disease; human subject; in vivo; insight; knock-down; knockout animal; lipid biosynthesis; lipid metabolism; liver transplantation; mRNA Expression; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel therapeutics; polyunsaturated phosphatidylcholine; protein expression; response; trafficking; transcription factor

Project Summary Sterol regulatory element-binding protein-1 (SREBP-1) is a pivotal activator of lipogenic enzymes involved in fatty acid synthesis. Transcription and proteolytic cleavage of SREBP-1 is tightly regulated by nutritional and hormonal factors under physiological and pathological conditions. Insulin dramatically increases the transcription of SREBP-1 mRNA primarily by increasing the activity of LXRs, and promotes post-translational processing of the protein. In ob/ob diabetic mouse livers, nuclear SREBP-1c is highly induced and contributes to the elevated hepatic fatty acid biosynthesis and steatosis. Besides sterols, other lipids have also been shown to regulate SREBP-1 processing, including unsaturated fatty acids (FAs) and phospholipids. The mechanisms by which phospholipids affect SREBP-1c expression remain to be resolved. Recent work from our lab has identified an LXR-Lpcat3 pathway that dynamically modulates membrane phospholipid (phosphatidylcholine and Phosphatidylethanolamine) composition in response to changes in cellular lipid metabolism. Activation of LXRs preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids through induction of the remodeling enzyme Lpcat3. Loss of Lpcat3 in liver selectively reduces arachidonoyl PC in liver membranes, and results in decreased membrane fluidity. Following on our initial work, we discovered that Lpcat3 regulates the LXR-mediated expression of genes involved in fatty acid biosynthesis. Our preliminary data suggest that Lpcat3 regulates the expression of lipogenic genes mainly through manipulating proteolytic cleavage of SREBP- 1. In this proposal, we aim to 1) Define the mechanisms by which Lpcat3 regulates SREBP-1 processing using Lpcat3 liver specific knockout primary hepatocytes and mice. 2) Determine whether Lpcat3 and phospholipid remodeling are involved in the regulation of SREBP-1c expression in liver under physiological or pathological conditions. We will assess if Lpcat3 mediates insulin-induced SREBP-1 expression in hepatocytes and in WT and LKO mouse livers during fasting/refeeding. We will examine the effect of Lpcat3 inhibition on SREBP-1 processing in ob/ob mice. Finally we will determine the involvement of Lpcat3 and phospholipid remodeling in human nonalcoholic fatty liver diseases (NAFLD). Given the close association between dysregulation of de novo lipogenesis and major human diseases, understanding the regulation of SREBP-1 expression is expect to provide novel insights into the molecular control of the development of fatty liver and dyslipidemia, and may suggest potential therapeutic opportunities for these diseases.

项目概要 甾醇调节元件结合蛋白-1 (SREBP-1) 是脂肪生成酶的关键激活剂 参与脂肪酸合成。 SREBP-1 的转录和蛋白水解裂解受到严格调控 生理和病理条件下的营养和激素因素。胰岛素急剧增加 SREBP-1 mRNA 的转录主要通过增加 LXR 的活性来实现，并促进翻译后 蛋白质的加工。在 ob/ob 糖尿病小鼠肝脏中，核 SREBP-1c 被高度诱导并有助于 导致肝脏脂肪酸生物合成升高和脂肪变性。除甾醇外，还显示了其他脂质 调节 SREBP-1 加工，包括不饱和脂肪酸 (FA) 和磷脂。机制 磷脂通过何种方式影响 SREBP-1c 表达仍有待解决。我们实验室最近的工作 确定了动态调节膜磷脂（磷脂酰胆碱和 磷脂酰乙醇胺）成分响应细胞脂质代谢的变化。 LXR 的激活 通过诱导优先驱动多不饱和脂肪酸掺入磷脂中 重塑酶Lpcat3。肝脏中 Lpcat3 的缺失选择性地减少肝膜中的花生四烯酰 PC， 并导致膜流动性下降。继我们的初步工作之后，我们发现 Lpcat3 调节 LXR介导的参与脂肪酸生物合成的基因表达。我们的初步数据表明 Lpcat3主要通过操纵SREBP-的蛋白水解裂解来调节脂肪生成基因的表达 1. 在本提案中，我们的目标是 1) 定义 Lpcat3 调节 SREBP-1 处理的机制，使用 Lpcat3 肝脏特异性敲除原代肝细胞和小鼠。 2) 判断是否Lpcat3和磷脂 重塑参与生理或病理状态下肝脏SREBP-1c表达的调节 状况。我们将评估 Lpcat3 是否介导肝细胞和 WT 中胰岛素诱导的 SREBP-1 表达 和禁食/再喂食期间 LKO 小鼠肝脏。我们将检查 Lpcat3 抑制对 SREBP-1 的影响 在 ob/ob 小鼠中进行处理。最后我们将确定 Lpcat3 和磷脂重构的参与 人类非酒精性脂肪肝疾病（NAFLD）。鉴于从头失调之间的密切联系 脂肪生成和人类主要疾病，了解SREBP-1表达的调控有望 为脂肪肝和血脂异常的发展的分子控制提供新的见解，并可能 提出这些疾病的潜在治疗机会。