Hepatic fat accumulation in nonalcoholic fatty liver disease: critical regulation by kisspeptin signaling

非酒精性脂肪性肝病中的肝脏脂肪积累：Kisspeptin 信号传导的关键调节

基本信息

批准号：
10612979
负责人：
Moshmi M Bhattacharya
金额：
$ 47.7万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-30 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612979
关键词：
Adult Affect Agonist Binding Biochemical Cicatrix Cirrhosis Coupled Data Demographic Factors Development Diet Disease Disease Progression Early Diagnosis Evaluation Exhibits Fatty Liver Fatty acid glycerol esters Female Fibrosis G-Protein-Coupled Receptors GTP-Binding Proteins Goals Government Hepatic Hepatocyte High Fat Diet Homeostasis Human In Vitro Inflammation Inflammatory Insulin Resistance KISS1 gene KISS1R gene Knock-out Knockout Mice Knowledge Laboratories Ligands Link Lipids Liver Liver Fibrosis Mass Spectrum Analysis Measures Messenger RNA Metabolic Metabolic Diseases Metabolic syndrome Molecular Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacotherapy Plasma Primary carcinoma of the liver cells Proteins Receptor Activation Receptor Inhibition Receptor Signaling Regulation Risk Role Severity of illness Signal Pathway Signal Transduction Source Staging Steatohepatitis Technical Expertise Testing Triglycerides United States United States National Institutes of Health Up-Regulation Virus Work chronic liver disease clinical biomarkers clinical diagnosis clinically relevant comparison control experience fatty acid oxidation feeding gain of function improved in vivo lipid biosynthesis lipid metabolism liver biopsy liver function loss of function male mortality mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel pandemic disease pharmacologic radiological imaging receptor receptor expression sensor therapeutic development therapeutic target translational approach

项目摘要

Obesity, a long-standing pandemic in the United States, is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common chronic liver disease globally, affecting about one third of adults, for which there is no approved medication. The first stage of NAFLD is steatosis (fatty liver), a condition that can progress to non-alcoholic steatohepatitis (NASH) where fat accumulation in the liver is associated with inflammation, fibrosis and scarring, resulting in the eventual loss of liver function. There is therefore a dire need to understand the molecular mechanisms underlying the development of fatty liver and NASH to create the first identified targets for medication. The liver produces a peptide known as kisspeptin (KP), that signals by binding a G protein-coupled receptor, the kisspeptin 1 receptor (KISS1R) expressed in the liver. The metabolic functions of KISS1R signaling in the liver, however, are not known. We found that hepatic KP/KISS1R expression are upregulated in high fat diet induced mouse model of NAFLD. We also observed that when mice lacking hepatic KISS1R were challenged with high fat diet-feeding, they showed increased hepatic steatosis, insulin resistance, and an upregulation of inflammatory and fibrosis markers, compared to controls on the same diet. Taken together, this data led us to hypothesize that hepatic KISS1R activation suppresses hepatic lipogenesis thus limiting fat accumulation and NASH development. The proposed work will decipher the mechanisms by which KISS1R signaling inhibits fatty liver and NASH. In Aim 1, we will investigate the mechanisms by which hepatic KISS1R signaling modulates hepatic lipid levels by inhibiting lipogenesis. In Aim 2, we will assess the impact of enhancing KISS1R signaling on the development of NAFLD. In Aim 3, we will study the clinical relevance of KP/KISS1R signaling pathway by measuring plasma KP levels in healthy subjects, NAFLD and NASH patients and assess whether plasma KP levels correlate with metabolic disease severity and other anthropometric, laboratory, radiographic and demographic features. Additionally, the expression and localization of hepatic KISS1R in NAFLD/NASH liver biopsies will be examined. Understanding this knowledge is important because it will shed light on using the KISS1R signaling pathway as a potential avenue to develop a novel pharmacological approach to reduce NAFLD and NASH.

肥胖症是美国长期存在的大流行，与非酒精性脂肪肝病（NAFLD）的风险增加有关。 NAFLD是全球最常见的慢性肝病，影响了大约三分之一的成年人，没有批准的药物。 NAFLD的第一阶段是脂肪变性（脂肪肝），这种疾病可以发展为非酒精性脂肪性肝炎（NASH），其中肝脏中的脂肪积累与炎症，纤维化和疤痕相关，从而导致最终的肝功能丧失。因此，迫切需要了解脂肪肝和NASH发展的分子机制，以创建第一个确定的药物靶标。肝脏会产生一种称为Kisspeptin（KP）的肽，该肽通过结合G蛋白偶联受体，在肝脏中表达的Kisspeptin 1受体（KISS1R）来信号。然而，肝脏中KISS1R信号的代谢功能尚不清楚。我们发现，在高脂饮食诱导的NAFLD小鼠模型中，肝KP/KISS1R表达上调。我们还观察到，与同一饮食对照相比，当缺乏肝KISS1R的小鼠受到高脂肪饮食喂养的挑战时，它们显示出增加的肝脂肪变性，胰岛素抵抗和炎症和纤维化标记的上调增加。综上所述，这些数据导致我们假设肝接吻激活抑制了肝脂肪生成，从而限制了脂肪的积累和NASH的发育。所提出的工作将破译Kiss1r信号抑制脂肪肝和NASH的机制。在AIM 1中，我们将研究肝KISS1R信号传导通过抑制脂质发生来调节肝脂质水平的机制。在AIM 2中，我们将评估增强KISS1R信号传导对NAFLD发展的影响。在AIM 3中，我们将通过测量健康受试者，NAFLD和NASH患者的血浆KP水平来研究KP/KISS1R信号通路的临床相关性，并评估血浆KP水平是否与代谢性疾病严重程度以及其他人体测量，实验室，放射线和射线学和人口统计学和人口统计学，放射线和人群特征相关。此外，将检查肝KISS1R在NAFLD/NASH肝活检中的表达和定位。理解这些知识很重要，因为它将阐明使用Kiss1r信号通路作为开发一种新型药理方法来减少NAFLD和NASH的潜在途径。