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 非酒精性脂肪肝病（NAFLD）影响美国成年人口的25％，与 肥胖，胰岛素抵抗和心血管疾病。此外，大约20％的NAFLD患者 （13-1600万人）发展肝纤维化，这与肝细胞癌较高的风险有关 肝硬化和肝衰竭。不幸的是，除了生活方式外，NAFLD几乎没有有效的治疗方法 修饰和肝移植。过多的中性脂质存储在脂质液滴（LDS）中 - 动态细胞器 根据细胞的代谢需求，迅速扩展和收缩。重要的是，LD形态和 抽象是由现有LD的融合或脂解确定的。最近的研究导致了发现 一种名为Basic的新型蛋白质，一种内质网状 - 脂肪液滴蛋白，可促进多眼 表型并增加棕色脂肪细胞中的脂质利用率。基本用白色和棕色脂肪表示 组织和肝脏。在脂肪细胞中，碱性抑制LD融合蛋白CIDEA和CIDEC，以防止膨胀 LD大小。 CIDEB是在肝脏中表达的主要CIDE蛋白，已显示可促进VLDL分泌， 减少甘油三酸酯和胆固醇的合成，并抑制肝细胞中的B氧化。但是， 肝脏需要较小的基本+ lds以进行最佳功能的生理或病理环境仍然存在 可以确定。有趣的是，全球，但不是针对基本脂肪的特定缺失，糖类的脂肪质量会减少 - 喂养小鼠，指出对全身能量平衡的依赖性影响。初步数据表明 Basic是PPARA靶基因，其表达是由禁食和西方饮食喂养高度诱导的。 碱性急性过表达减少血浆脂质，表明该蛋白质调节肝脂质 代谢。拟议的研究计划将通过表征如何来阐明肝脏作用机理 基本调节LD生物学并在体外定义分子相互作用伙伴（AIM 1A）。此外， 受肝碱性表达影响（β-氧化，脂肪生成，脂蛋白分泌）影响的途径将是 确定（目标1b）。在小鼠中使用增益和功能丧失方法的体内研究将表征 基本在禁食中的作用和对高脂饮食喂养的响应（AIM 2）。拟议的目标的完成将 提供新的PPARA靶基因功能的见解，这将有助于增长 了解肝脂质液滴生物学，并可能揭示出新的治疗机会 血脂异常和肝脂肪变性。