Metabolic impact of FGF-21 in adipose tissue and liver of PLWH

FGF-21 对感染者脂肪组织和肝脏代谢的影响

• 批准号: 10259862
• 负责人: Jordan E Lake
• 金额: $ 65万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10259862
• 关键词: Adipocytes; Adipose tissue; Affect; Blood; Body fat; Brown Fat; Chronic Disease; Clinical; Complex; Coupled; Data; Defect; Development; Diabetes Mellitus; Disease; Dissection; Dyslipidemias; Endocrine; Energy Metabolism; Esterification; Exhibits; Expenditure; Fasting; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Gene Deletion; Gene Expression Regulation; Glucose; Goals; HIV; HIV Infections; HIV therapy; Heart Diseases; Hepatic; Hormones; Immunology; Impairment; Indirect Calorimetry; Insulin; Insulin Resistance; Intra-abdominal; Kinetics; Lead; Link; Lipids; Lipolysis; Liver; Liver Failure; Liver diseases; Measures; Metabolic; Metabolic Diseases; Molecular; Mus; Patients; Persons; Pharmaceutical Preparations; Physiological; Physiology; Research; Serum; Shapes; Signal Transduction; Testing; Thermogenesis; Tissues; Transgenic Organisms; Viral; Virus; Work; abdominal fat; antiretroviral therapy; comorbidity; energy balance; fatty acid oxidation; fibroblast growth factor 21; glucose metabolism; improved; insulin sensitizing drugs; knockout gene; lifestyle intervention; lipid metabolism; liver metabolism; metabolic phenotype; mouse model; new therapeutic target; novel therapeutics; subcutaneous; targeted treatment; therapeutic target; vpr Gene Products; wasting

ABSTRACT HIV and antiretroviral therapy (ART) are associated with adipose tissue (AT) dysfunction and systemic metabolic alterations, including intra-abdominal fat accumulation, fatty liver disease, dyslipidemia, and insulin resistance. Treatment of these defects using conventional drugs and lifestyle interventions has been minimally effective. Viral factors and ART contribute to the complex pathophysiology of these disease states in persons living with HIV (PLWH). Still, the mechanisms that link viral factors and ART to defective AT and hepatic metabolism remain incompletely understood. We have demonstrated in mouse models that the HIV accessory protein Vpr is sufficient to cause all the cardinal manifestations of HIV-associated metabolic disease. The Vpr mice also have high levels of FGF21 and increased subcutaneous AT thermogenesis. The current proposal aims to establish mechanistic connections between increased FGF21 levels, white AT thermogenesis, and the observed metabolic abnormalities in Vpr mice and PLWH. Our central hypothesis is that Vpr expression alters the metabolic effects of FGF21, altering AT and hepatic function and inducing maladaptive browning of subcutaneous white AT. We will test this hypothesis by achieving the following Specific Aims: 1) Determine how Vpr exposure affects white AT thermogenesis in mice; 2) Demonstrate how FGF21 shapes the metabolic abnormalities of Vpr mice; 3) Establish relationships between FGF21’s endocrine actions and defects of lipid and glucose metabolism and subcutaneous white AT function in PLWH on suppressive ART. Our research plan will provide detailed dissection of the relationships between HIV-associated metabolic disease and FGF21 physiology, molecular mechanisms of thermogenesis and AT physiology, and immunology. The project will reveal mechanisms of unique metabolic defects in Vpr mouse models that recapitulate those in PLWH, and elucidate how FGF21’s endocrine functions contribute to HIV-associated metabolic abnormalities in PLWH on ART. Ultimately, this translational work will identify mechanisms of HIV-specific metabolic alterations and may identify therapeutic targets that can be exploited to minimize the long-term clinical burden of metabolic disease in PLWH.

抽象的 HIV和前视疗法（ART）与脂肪组织（AT）功能障碍和 全身代谢改变，包括腹腔内脂肪的积累，脂肪肝病， 血脂血症和胰岛素抵抗。 生活方式干预措施至少有效。 患有艾滋病毒的人（PLWH）的复杂病理生理学 将病毒因素和艺术与肝代谢有缺陷联系起来的机制仍然存在 我们在鼠标模型中证明了艾滋病毒附件 提供蛋白质VPR可引起与HIV相关代谢的所有基本表现 疾病。 当前的建议旨在建立机械连接 FGF21水平升高，热发生时白色以及观察到的代谢异常 VPR小鼠和PLWH。 FGF21，在肝功能上改变并诱发皮下不良适应性褐变 白色。 VPR暴露在小鼠中如何影响白色； 2） VPR小鼠的代谢异常； 3） 脂质和葡萄糖代谢的作用和缺陷以及功能下的皮下白色 抑制艺术的PLWH。 HIV相关的代谢疾病与FGF21生理学，分子之间的关系 生理学和生理学的机制和免疫学会揭示 VPR小鼠模型中独特代谢缺陷的机制，这些机制概括了PLWH的机制， 并阐明FGF21的内分泌功能如何促进艾滋病毒的代谢 Art的PLWH异常，这个翻译工作世界。 HIV特异性的代谢替代性，并可能识别可以利用的治疗靶标 最大程度地减少PLWH代谢疾病的长期临床负担。