Regulation of hepatic lipid metabolism by novel protein BASIC

新型蛋白质 BASIC 对肝脏脂质代谢的调节

• 批准号: 10535352
• 负责人: Lauren F Uchiyama
• 金额: $ 3.83万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535352
• 关键词: Acute; Adipocytes; Adipose tissue; Adult; Affect; Albumins; Atherosclerosis; Binding; Biochemical; Biological Assay; Biology; Body Composition; Brown Fat; C-terminal; Cardiovascular Diseases; Cells; Chimeric Proteins; Cholesterol; Cirrhosis; Data; Diabetes Mellitus; Dyslipidemias; Endoplasmic Reticulum; Energy Metabolism; Fasting; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Gene Expression; Genes; Genus Hippocampus; Glucose; Goals; Hepatic; Hepatocyte; High Fat Diet; Histology; Homeostasis; Hypertriglyceridemia; Immunoprecipitation; Impairment; In Vitro; Indirect Calorimetry; Insulin Resistance; Intervention; Ketones; Knock-out; Laboratories; Life Style Modification; Lipids; Lipolysis; Lipoproteins; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Metabolic; Metabolic Diseases; Metabolism; Microscopy; Mitochondria; Modeling; Morphology; Mus; N-terminal; Names; Obesity; Organelles; Pathologic; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Physiology; Plasma; Population; Primary carcinoma of the liver cells; Production; Proteins; Proteomics; Regulation; Research; Resolution; Respiration; Role; Testing; Therapeutic; Therapeutic Intervention; Thermogenesis; Tissues; Triglycerides; United States; Very low density lipoprotein; adrenergic stress; base; blood glucose regulation; effective therapy; energy balance; fatty acid oxidation; feeding; high risk; in vivo; inhibitor; insight; insulin tolerance; lipid biosynthesis; lipid metabolism; liver development; liver transplantation; loss of function; mouse model; non-alcoholic fatty liver; non-alcoholic fatty liver disease; novel; overexpression; oxidation; prevent; protein expression; response; therapeutic target; transcriptome sequencing; vector; very low density lipoprotein triglyceride; western diet

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) affects 25% of the US adult population and is associated with obesity, insulin resistance and cardiovascular disease. Furthermore, approximately 20% of NAFLD patients (13-16 million people) develop liver fibrosis, which is associated with a higher risk of hepatocellular carcinoma, cirrhosis and liver failure. Unfortunately, there are few effective treatments for NAFLD, aside from lifestyle modification and liver transplant. Excess neutral lipids are stored in lipid droplets (LDs)–dynamic organelles that quickly expand and shrink depending on the metabolic needs of the cell. Importantly, LD morphology and abundance are determined by the fusion or lipolysis of existing LDs. Recent studies have led to the discovery of a novel protein named BASIC, an endoplasmic reticulum-lipid droplet protein that promotes a multilocular phenotype and increases lipid utilization in brown adipocytes. BASIC is expressed in white and brown adipose tissue, and liver. In adipocytes, BASIC inhibits LD fusion proteins CIDEA and CIDEC, preventing expansion of LD size. CIDEB, the primary CIDE protein expressed in liver, has been shown to promote VLDL secretion, decrease triglyceride and cholesterol synthesis, and inhibit b-oxidation in hepatocytes. However, the physiologic or pathologic contexts in which the liver requires small, BASIC+ LDs for optimal function remain to be determined. Interestingly, global, but not adipose-specific deletion of BASIC decreases fat mass in chow- fed mice, pointing to adipose-independent effects on systemic energy balance. Preliminary data indicate that BASIC is a PPARa target gene whose expression is highly induced by both fasting and western diet feeding. Acute overexpression of BASIC decreases plasma lipids, suggesting this protein regulates hepatic lipid metabolism. The proposed research plan will elucidate the hepatic mechanism of action by characterizing how BASIC regulates LD biology and define molecular interaction partners in vitro (Aim 1a). Furthermore, the pathway(s) affected by hepatic BASIC expression (beta-oxidation, lipogenesis, lipoprotein secretion) will be determined (Aim 1b). In vivo studies using gain- and loss-of-function approaches in mice will characterize the role of BASIC in fasting and in response to high-fat diet feeding (Aim 2). Completion of the proposed aims will provide insight for the function of a novel PPARa target gene, which will contribute to the growing understanding of hepatic lipid droplet biology and may reveal novel opportunities for therapeutics in dyslipidemia and hepatic steatosis.

项目摘要 非酒精性脂肪性肝病（NAFLD）影响25%的美国成年人口，并与 肥胖、胰岛素抵抗和心血管疾病。此外，大约20%的NAFLD患者 （1300万至1600万人）发生肝纤维化，这与肝细胞癌的高风险相关， 肝硬化和肝功能衰竭。不幸的是，除了生活方式外，NAFLD的有效治疗方法很少 改造和肝移植过量的中性脂质储存在脂滴（LDs）中-动态细胞器 根据细胞的代谢需要迅速膨胀和收缩。重要的是，LD形态和 丰度由现有LD的融合或脂解决定。最近的研究发现 一种名为BASIC的新型蛋白质，一种内质网脂滴蛋白， 表型和增加棕色脂肪细胞中的脂质利用。BASIC在白色和棕色脂肪中表达 组织和肝脏。在脂肪细胞中，BASIC抑制LD融合蛋白CIDEA和CIDEC，阻止脂肪细胞的扩增。 LD尺寸。CIDEB是在肝脏中表达的主要锡德蛋白，已显示促进VLDL分泌， 降低甘油三酯和胆固醇合成，并抑制肝细胞中的β-氧化。但 肝脏需要小的BASIC+ LD以实现最佳功能的生理或病理背景仍然是 被确定。有趣的是，整体，但不是脂肪特异性的BASIC缺失减少了食物中的脂肪量。 喂养的小鼠，指出脂肪对全身能量平衡的非依赖性影响。初步数据表明 BASIC是PPARa靶基因，其表达被禁食和西方饮食喂养高度诱导。 急性过表达BASIC可降低血脂，提示该蛋白可调节肝脏脂质 新陈代谢.拟议的研究计划将阐明肝脏的作用机制， BASIC在体外调节LD生物学并定义分子相互作用伴侣（Aim 1a）。而且 受肝脏BASIC表达影响的途径（β-氧化、脂肪生成、脂蛋白分泌）将被 目标1b）。在小鼠中使用功能获得和丧失方法的体内研究将表征 BASIC在禁食和高脂饮食喂养中的作用（目的2）。实现拟议目标将 为新型PPARa靶基因的功能提供见解，这将有助于促进 了解肝脂滴生物学，并可能揭示新的治疗机会， 血脂异常和肝脂肪变性。