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: 10645095
• 负责人: Lauren F Uchiyama
• 金额: $ 3.92万
• 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/10645095
• 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; Gene Expression Profiling; 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; Mitochondria; Modeling; Morphology; Mus; N-terminal; Names; Obesity; Organelles; Pathologic; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Plasma; Population; Primary carcinoma of the liver cells; Production; Proteins; Proteomics; Regulation; Research; Respiration; Role; Spirometry; Testing; Therapeutic; Therapeutic Intervention; Thermogenesis; Tissues; Triglycerides; United States; Very low density lipoprotein; adrenergic stress; blood glucose regulation; effective therapy; energy balance; fatty acid oxidation; feeding; gain of function; 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; pharmacologic; prevent; protein expression; response; superresolution microscopy; 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.

项目总结