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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要非酒精性脂肪肝 (NAFLD) 影响 25% 的美国成年人口，并且与此外，大约20%的NAFLD患者患有肥胖症、胰岛素抵抗和心血管疾病。（13-1600 万人）出现肝纤维化，这与肝细胞癌的较高风险相关，不幸的是，除了生活方式之外，NAFLD 几乎没有有效的治疗方法。修饰和肝移植中过量的中性脂质储存在脂滴（LD）-动态细胞器中。重要的是，LD 的形态和大小会根据细胞的代谢需求而快速膨胀和收缩。最近的研究发现，丰度是由现有 LD 的融合或脂肪分解决定的。一种名为 BASIC 的新型蛋白质的研究，这是一种内质网脂滴蛋白质，可促进多室 BASIC 在白色和棕色脂肪中表达。在脂肪细胞中，BASIC 抑制 LD 融合蛋白 CIDEA 和 CIDEC，从而防止脂肪细胞的扩张。 LD 大小 CIDEB 是肝脏中表达的主要 CIDE 蛋白，已被证明可以促进 VLDL 分泌，减少甘油三酯和胆固醇的合成，并抑制肝细胞中的 b-氧化。肝脏需要小的 BASIC+ LD 才能实现最佳功能的生理或病理环境仍然需要提示性地确定，BASIC 的整体而非脂肪特异性删除会降低食物中的脂肪量。喂食小鼠，表明对全身能量平衡的影响与脂肪无关。 BASIC 是 PPARa 靶基因，其表达受到禁食和西方饮食喂养的高度诱导。 BASIC 的急性过度表达会降低血浆脂质，表明该蛋白可调节肝脂质拟议的研究计划将通过表征如何代谢来阐明肝脏的作用机制。 BASIC 规范 LD 生物学并定义体外分子相互作用伙伴（目标 1a）。受肝脏 BASIC 表达（β-氧化、脂肪生成、脂蛋白分泌）影响的途径将确定（目标 1b）。使用小鼠功能获得和丧失方法进行的体内研究将表征 BASIC 在禁食和应对高脂肪饮食喂养中的作用（目标 2）将完成。为新的 PPARa 靶基因的功能提供见解，这将有助于促进了解肝脏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。