SHP-regulation of Lipid and Lipoprotein Metabolism

描述(申请人提供)：目前肥胖和代谢综合征的流行已显著增加脂肪肝的频率，这可能会导致纤维化、肝硬变、终末期肝病和肝癌。脂肪肝(脂肪变性)影响着美国大约30%的人。SHP(小异二聚体)是一种核受体，调节代谢综合征的几个主要方面，包括肥胖、血脂异常和胰岛素敏感性。这项研究的主要目的是确定SHP缺乏如何预防小鼠脂肪肝。中心假说是，SHP以对脂肪肝的发展有重要影响的方式调节肝脏的脂肪酸摄取和氧化(目标1)和肝脂蛋白分解代谢(目标2)。据预测，SHP调节的丧失会增加脂质氧化，减少脂质摄取，从而协调地减少脂肪在肝脏中的积累。这一假说建立在初步结果的基础上，表明：a)SHP缺乏可减少肝脏脂肪堆积，防止高胆固醇或高脂肪饮食诱导的脂肪变性；b)肥胖糖尿病小鼠(OB/OB)的脂肪肝可通过缺乏SHP(OB/SHP-/-鼠)来预防；c)PPAR？途径下调，而PPARa途径在SHP缺失的小鼠中上调；d)脂蛋白清除和高密度脂蛋白胆固醇摄取减少。一旦确定了SHP调控这些途径中关键基因转录的机制，就应该有可能通过小分子靶向这些过程来改善或预防脂肪肝(长期目标)。其具体目的是确定：(1)SHP调节肝脏脂肪酸摄取和氧化的机制；(2)SHP调节脂蛋白分解代谢的机制。识别SHP的特定功能和预防SHP缺陷小鼠脂肪肝的机制将为治疗或预防患者脂肪肝提供机制洞察力和新的方法。

DESCRIPTION (provided by applicant): The current epidemic of obesity and the metabolic syndrome has dramatically increased the frequency of fatty liver, which can cause fibrosis, cirrhosis, end-stage liver disease and hepatoma. Fatty liver (steatosis) affects approximately 30 percent of the people in the USA. SHP (small heterodimer partner) is a nuclear receptor that regulates several major aspects of the metabolic syndrome, including obesity, dyslipidemia and insulin sensitivity. The major objective of this study is to determine how SHP-deficiency prevents fatty liver in mice. The central hypothesis is that SHP regulates hepatic fatty acid uptake and oxidation (Aim #1) and hepatic lipoprotein catabolism (Aim #2) in a way that has a major influence on the development of fatty liver. The loss of SHP regulation is predicted to increase lipid oxidation, and decrease lipid uptake, which coordinately decreases fat accumulation in the liver. This hypothesis is based on the Preliminary Results, demonstrating that: a) SHP deficiency in SHP-/- mice decreases hepatic lipid accumulation and protects against high-cholesterol or high-fat diet induced steatosis; b) fatty liver in obese diabetic mice (OB/OB) is prevented by the absence of SHP (OB/SHP-/- mice); c) the PPAR? pathway is down-regulated, whereas the PPARa pathway is upregulated in SHP-null mice; and d) lipoprotein clearance and HDL cholesterol uptake is decreased by SHP-deficiency. Once the mechanisms of SHP regulated transcription of critical genes in these pathways are defined, it should be possible to target these processes with small molecules to improve or prevent fatty liver disease (long-term goal). The Specific Aims are to define: (1) mechanisms for SHP regulation of hepatic fatty acid uptake and oxidation; and, (2) mechanism for SHP regulation of lipoprotein catabolism. Identifying specific functions of SHP and the mechanisms preventing fatty liver in SHP deficient mice should provide mechanistic insight and novel approaches to treating or preventing fatty liver in patients.