Hepatic Lipid Mobilization by Nuclear Hormone Receptors

核激素受体的肝脂质动员

• 批准号: 8439573
• 负责人: YOON-KWANG LEE
• 金额: $ 29.68万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-10 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439573
• 关键词: Adenoviruses; Adipocytes; Adipose tissue; Architecture; Body Weight; Chronic; DNA Binding Domain; Development; Diabetes Mellitus; Diet; Dietary Fats; Disease; Disease Progression; Electrophoretic Mobility Shift Assay; Enhancers; Etiology; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Gene Expression; Hepatic; Homeostasis; Human; Impaired fasting glycaemia; In Vitro; Infection; Ingestion; Insulin Resistance; Intervention; Knock-out; Leptin; Ligands; Lipid Mobilization; Lipids; Liver; Liver diseases; Metabolic; Metabolic Pathway; Metabolic syndrome; Molecular; Mus; NR0B2 gene; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Nuclear Orphan Receptor; Nuclear Receptors; Obesity; Orphan; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Physiological; Play; Prevention; Proteins; Publishing; Receptor Activation; Regulation; Regulatory Element; Regulatory Pathway; Reporting; Repression; Retinoic Acid Receptor; Risk Factors; Role; Series; Signal Transduction; Solid; Specificity; Testing; Tissue Differentiation; Transactivation; Transcription Repressor/Corepressor; Transcriptional Regulation; Transfection; Transgenic Mice; Tretinoin; Triglycerides; base; cohort; congenic; derepression; efficacy testing; fatty acid oxidation; feeding; glucose metabolism; human subject; in vivo; insight; lipid metabolism; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; overexpression; promoter; protein protein interaction; public health relevance; research study; response; small heterodimer partner protein; therapeutic development; transcription factor

DESCRIPTION (provided by applicant): Hepatic steatosis is associated with nonalcoholic fatty liver disease (NAFLD), which can progress to nonalcoholic steatohepatitis (NASH). NAFLD is also a leading risk factor for the development of impaired fasting glucose and type 2 diabetes. Small heterodimer partner (SHP, NR0B2) belongs to the nuclear hormone receptor superfamily. Earlier molecular studies suggested that SHP plays a role in glucose and lipid metabolism. Our studies with congenic SHP-/- mice showed that SHP regulates hepatic triglyceride (TG) storage in response to excess dietary fat ingestion, and its deficiency protects against development of hepatic steatosis. This protection against fatty liver development in SHP-/- mice results in part from elevated-fatty acid oxidation due to derepression of PPAR? transcriptional activity, but also to lower expression of PPAR?2, a major lipogenic transcription factor. Marked elevation of hepatic PPAR? expression has been observed in numerous mouse models of NAFLD and human patients with the disorder. Integrating our own preliminary results with published studies, we have identified a novel transcriptional cascade in which SHP regulates PPAR? expression. In this new regulatory pathway, SHP represses the ability of the retinoic acid receptor (RAR) to activate expression of hairy and enhancer split 6 (Hes6) a transcriptional corepressor that has recently been reported to repress PPAR?2 via inhibition of HNF4? transactivation. In accord with this, we have shown that RAR activation by its natural ligand all-trans retinoic acid (atRA) alleviates hepatic steatosis. Thus we hypothesize that SHP and atRA/RAR can function coordinately to regulate hepatic lipid accumulation. In order to critically test the significance o our proposed regulatory cascade, we will 1) define the regulatory role of SHP and atRA in the expression of Hes6, then 2) examine the functional interactions of SHP and atRA/RAR in modulating fat accumulation in mouse models of NAFLD, and finally 3) test the linkage between Hes6 and fat mobilization using Hes6 overexpression or silencing. Our studies of this novel transcriptional regulatory network will provide insights into the development of hepatic steatosis and crucial avenues into the prevention and treatment of a disorder that is a major contributor in the development of the metabolic syndrome.

描述（由申请方提供）：肝脏脂肪变性与非酒精性脂肪性肝病（NAFLD）相关，后者可进展为非酒精性脂肪性肝炎（NASH）。NAFLD也是空腹血糖受损和2型糖尿病发展的主要危险因素。小异源二聚体伴侣（SHP，NR 0 B2）属于核激素受体超家族。早期的分子研究表明，SHP在糖和脂质代谢中起作用。我们对同类SHP-/-小鼠的研究表明，SHP调节肝脏甘油三酯（TG）储存，以应对过量的膳食脂肪摄入，其缺乏可防止肝脂肪变性的发展。这种对SHP-/-小鼠脂肪肝发展的保护作用部分是由于PPAR去抑制引起的脂肪酸氧化升高。转录活性，但也降低表达的过氧化物酶体增殖物激活受体？2，一个主要的脂肪生成转录因子。肝脏过氧化物酶体增殖物激活受体显著升高？已经在许多NAFLD小鼠模型和患有该疾病的人类患者中观察到表达。结合我们自己的初步结果与已发表的研究，我们已经确定了一种新的转录级联反应，其中SHP调节过氧化物酶体增殖物激活受体？表情在这一新的调控途径中，SHP抑制视黄酸受体（RAR）激活毛状和增强子分裂6（Hes 6）的表达的能力，这是一种转录辅抑制因子，最近被报道抑制PPAR？2通过抑制HNF 4？反式激活与此雅阁，我们已经证明RAR被其天然配体全反式维甲酸（atRA）激活可加重肝脂肪变性。因此，我们推测SHP和atRA/RAR可以协同调节肝脏脂质积聚。为了严格测试我们提出的调节级联的意义，我们将1）定义SHP和atRA在Hes 6表达中的调节作用，然后2）检查SHP和atRA/RAR在调节NAFLD小鼠模型中的脂肪积累中的功能相互作用，最后3）使用Hes 6过表达或沉默来测试Hes 6与脂肪动员之间的联系。我们对这种新型转录调控网络的研究将为肝脏脂肪变性的发展提供深入见解，并为预防和治疗代谢综合征发展的主要贡献者的疾病提供重要途径。