SHP-regulation of Lipid and Lipoprotein Metabolism

描述（由申请人提供）：目前肥胖和代谢综合征的流行已经显著增加了脂肪肝的频率，脂肪肝可以导致纤维化、肝硬化、终末期肝病和肝癌。脂肪肝（脂肪变性）影响美国约30%的人。SHP（小异二聚体伴侣）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。本研究的主要目的是确定SHP缺乏如何预防小鼠脂肪肝。中心假设是SHP调节肝脂肪酸摄取和氧化（目标#1）和肝脂蛋白催化剂（目标#2）的方式对脂肪肝的发展有重大影响。预计SHP调节的丧失会增加脂质氧化，并减少脂质摄取，这会协调地减少肝脏中的脂肪积累。 该假设基于初步结果，证明：a）SHP-/-小鼠中的SHP缺乏降低了肝脏脂质积聚并保护免于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）中的脂肪肝通过SHP缺乏（OB/SHP-/-小鼠）来预防; c）PPAR？在SHP缺失小鼠中，PPARa途径下调，而PPARa途径上调;和d）脂蛋白清除和HDL胆固醇摄取因SHP缺乏而降低。一旦确定了SHP调节这些途径中关键基因转录的机制，就有可能用小分子靶向这些过程，以改善或预防脂肪肝疾病（长期目标）。具体目的是确定：（1）SHP调节肝脂肪酸摄取和氧化的机制;和（2）SHP调节脂蛋白催化剂的机制。在SHP缺陷小鼠中识别SHP的特定功能和预防脂肪肝的机制应该为治疗或预防患者的脂肪肝提供机制见解和新方法。

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.