Mechanism of SREBP Cleavage Activating Protein Golgi-to-ER Recycling

SREBP 裂解激活蛋白高尔基体至内质网回收的机制

• 批准号: 9008911
• 负责人: PETER J. ESPENSHADE
• 金额: $ 28.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-16 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9008911
• 关键词: Affect; Ammonium Chloride; Binding; Binding Proteins; Cell Line; Cell Maintenance; Cholesterol; Coat Protein Complex I; Cultured Cells; Data; Development; Diabetes Mellitus; Diet; Disease; Ensure; Epidemic; Failure; Fatty Acids; Fatty Liver; Genetic; Golgi Apparatus; Helix-Turn-Helix Motifs; Hepatic; Homeostasis; Incidence; Insulin; Leucine Zippers; Lipids; Liver; Liver Cirrhosis; Liver Failure; Liver diseases; Lysosomes; Malignant neoplasm of liver; Measures; Mediating; Membrane; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Pathway interactions; Patients; Peptide Hydrolases; Plasma; Population; Prevalence; Proteins; Proteolysis; Proteomics; Public Health; Recycling; Regulation; Regulatory Element; Risk Factors; Rodent Model; Role; SCAP protein; Site; Site-Directed Mutagenesis; Staging; Steatohepatitis; Sterols; Testing; Triglycerides; base; chronic liver disease; diabetic; fatty acid oxidation; inhibitor/antagonist; insight; lipid biosynthesis; non-alcoholic fatty liver; novel; novel therapeutics; prevent; protein complex; protein degradation; protein transport; public health relevance; research study; site-1 protease; transcription factor; uptake

 DESCRIPTION (provided by applicant): The incidence of type 2 diabetes mellitus (T2DM) has increased due to the obesity epidemic, and diabetes is projected to affect one-quarter of the U.S. population by 2050. Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the world with a prevalence estimated to be approximately 30% in the US. Importantly, T2DM is a major risk factor for NAFLD with ~70% of T2DM patients having a fatty liver. In patients with T2DM, NAFLD is a leading cause of end-stage liver failure as fatty liver can progress to steatohepatitis, liver cirrhosis, and ultimately liver cancer. For these reasons, a detailed understanding of the mechanisms underlying NAFLD is a public health imperative. Hepatic lipid accumulation results from disruptions to lipid homeostasis at multiple levels, including lipid synthesis. Membrane-bound, basic helix-loop-helix leucine zipper transcription factors called sterol regulatory element-binding proteins (SREBPs) are master regulators of cellular lipogenesis, controlling synthesis of cholesterol, fatty acids and triglycerides. SREBP cleavage activating protein (SCAP) binds and transports ER-localized SREBPs to the Golgi where they are proteolytically activated by the sequential action of the Site-1 and Site-2 proteases. SCAP then recycles to the ER for additional rounds of SREBP cleavage. Excitingly, recent data demonstrate that SCAP is required for development of fatty liver in both genetic and dietary rodent models of obesity-induced diabetes, making SCAP a target for the treatment of NAFLD. Based on preliminary studies, we hypothesize that proper regulation of lipid homeostasis requires SCAP recycling from the Golgi to the ER. To test this hypothesis, we will define the mechanism of SCAP recycling and evaluate control of lipid homeostasis when recycling is disrupted. We propose the following specific aims: AIM 1. TO TEST DIRECTLY WHETHER SCAP RECYCLlNG REQUIRES SREBP CLEAVAGE AT SITE-1. AIM 2. TO TEST WHETHER REGULATION OF LIPID HOMEOSTASIS REQUIRES SCAP RECYCLING. AIM 3. TO DETERMINE MACHINERY REQUIRED FOR SCAP RECYCLING. SCAP is a central regulator of hepatic lipogenesis whose loss prevents development of fatty liver disease. Our proposed experiments will define the mechanism for SCAP Golgi-to-ER recycling, an unexplored half of the SREBP pathway. These fundamental studies will reveal novel control points for lipid homeostasis, providing new therapeutic opportunities for this increasingly common disease.

 描述(申请人提供)：由于肥胖症流行，2型糖尿病(T2 DM)的发病率有所增加，预计到2050年，糖尿病将影响四分之一的美国人口。非酒精性脂肪性肝病(NAFLD)是世界上最常见的慢性肝病，在美国的患病率估计约为30%。重要的是，T2 DM是NAFLD的主要危险因素，约70%的T2 DM患者有脂肪肝。在T2 DM患者中，NAFLD是导致终末期肝功能衰竭的主要原因，因为脂肪肝可以进展为脂肪性肝炎、肝硬变，并最终发展为肝癌。出于这些原因，详细了解NAFLD的潜在机制是公共卫生的当务之急。肝脏脂肪堆积是由多个水平上的脂质动态平衡的破坏造成的，包括脂质合成。膜结合的碱性螺旋-环-亮氨酸拉链转录因子称为固醇调节元件结合蛋白(SREBPs)，是细胞脂肪生成的主要调节因子，控制胆固醇、脂肪酸和甘油三酯的合成。SREBP裂解激活蛋白(SCAP)结合并运输ER定位的SREBPs到高尔基体，在那里它们被Site-1和Site-2酶的顺序作用而被蛋白水解性激活。然后，SCAP循环到ER进行额外几轮SREBP切割。令人兴奋的是，最近的数据表明，在肥胖诱导的糖尿病的遗传和饮食啮齿动物模型中，SCAP对于脂肪肝的发生都是必需的，这使得SCAP成为治疗NAFLD的靶点。在初步研究的基础上，我们假设脂质平衡的适当调节需要SCAP从高尔基体到内质网的循环。为了验证这一假说，我们将定义SCAP循环的机制，并评估当循环被破坏时对脂质稳态的控制。我们提出了以下具体目标：目的1.直接测试SCAP RECYCLlNG是否需要SREBP在1位点切割。目的2.测试脂质平衡的调节是否需要SCAP循环。目的3.确定SCAP回收所需的机械。SCAP是肝脏脂肪生成的中枢调节因子，其缺失可防止脂肪肝的发生。我们拟议的实验将定义SCAP高尔基体到内质网循环的机制，这是SREBP途径中尚未探索的一半。这些基础研究将揭示脂质稳态的新控制点，为这种日益常见的疾病提供新的治疗机会。