Regulation of hepatic lipid metabolism by novel protein BASIC

项目总结 非酒精性脂肪性肝病(NAFLD)影响着25%的美国成年人，与 肥胖、胰岛素抵抗和心血管疾病。此外，大约20%的非酒精性脂肪肝患者 (1,300-1,600万人)发展为肝纤维化，这与患肝细胞癌的风险更高有关， 肝硬变和肝功能衰竭。不幸的是，除了生活方式之外，治疗非酒精性脂肪肝的有效方法很少。 改造和肝移植。过量的中性脂质储存在脂滴(LDS)-动态细胞器中 根据细胞的新陈代谢需求，它会迅速膨胀和缩小。重要的是，LD的形态和 丰度由现有LDs的融合或脂解作用决定。最近的研究导致了这一发现 一种名为BASIC的新蛋白，一种内质网-脂滴蛋白，促进多房 棕色脂肪细胞的表型和增加脂肪的利用。碱性脂肪表现为白色和棕色脂肪。 组织和肝脏。在脂肪细胞中，BASIC抑制LD融合蛋白CIDEA和CIDEC，阻止 身份证大小。CIDEB是在肝脏表达的主要CIDE蛋白，已被证明能促进VLDL的分泌。 减少肝细胞内甘油三酯和胆固醇的合成，抑制b-氧化。然而， 生理或病理情况下，肝脏需要较小的基础+LDs才能达到最佳功能 要下定决心。有趣的是，BASIC基因的全局缺失，而不是特定于脂肪的缺失，可以减少食物中的脂肪质量。 喂养小鼠，指出脂肪非依赖性对全身能量平衡的影响。初步数据显示， BASIC是一个PPARa靶基因，其表达受到禁食和西方饮食喂养的高度诱导。 BASIC蛋白急性过表达可降低血脂，提示该蛋白调节肝脏脂质 新陈代谢。拟议的研究计划将通过表征肝脏的作用机制来阐明其作用机制。 BASIC调节LD生物学并定义体外分子相互作用伙伴(目标1a)。此外， 受肝脏基础表达(β-氧化、脂肪生成、脂蛋白分泌)影响的途径(S)将是 已确定(目标1b)。利用小鼠的功能获得和丧失方法进行的体内研究将表征 基础饮食在禁食和对高脂饮食喂养的反应中的作用(目标2)。完成拟议的目标将 为新的PPARa靶基因的功能提供洞察，这将有助于 了解肝脏脂滴的生物学，可能为治疗提供新的机会 血脂异常和肝脏脂肪变性。

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.