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

• 批准号: 10444589
• 负责人: Moshmi M Bhattacharya
• 金额: $ 51.53万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-30 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10444589
• 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 Protein alpha Subunits, Gs; 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; Lead; Ligands; Light; 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; Pharmacology; Pharmacotherapy; Plasma; Primary carcinoma of the liver cells; Proteins; Receptor Activation; 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; base; chronic liver disease; clinical biomarkers; clinical diagnosis; clinically relevant; experience; fatty acid oxidation; feeding; gain of function; improved; in vivo; lipid biosynthesis; lipid metabolism; liver biopsy; liver function; male; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; pandemic disease; radiological imaging; receptor; receptor expression; sensor; therapeutic development; therapeutic target; translational approach

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.

肥胖是美国长期流行的疾病，与非酒精性脂肪性肝病（NAFLD）的风险增加有关。NAFLD是全球最常见的慢性肝病，影响约三分之一的成年人，目前尚无批准的药物。NAFLD的第一阶段是脂肪变性（脂肪肝），这种情况可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、纤维化和瘢痕形成相关，最终导致肝功能丧失。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点。肝脏产生一种被称为kisspeptin （KP）的肽，它通过结合肝脏中表达的G蛋白偶联受体kisspeptin 1受体（KISS1R）来发出信号。然而，KISS1R信号在肝脏中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，肝脏KP/KISS1R表达上调。我们还观察到，当缺乏肝脏KISS1R的小鼠以高脂肪饮食喂养时，与相同饮食的对照组相比，它们表现出肝脏脂肪变性、胰岛素抵抗以及炎症和纤维化标志物的上调。综上所述，这些数据使我们假设肝脏KISS1R激活抑制肝脏脂肪生成，从而限制脂肪积累和NASH的发展。这项工作将破译KISS1R信号抑制脂肪肝和NASH的机制。在目的1中，我们将研究肝脏KISS1R信号通过抑制脂肪生成来调节肝脏脂质水平的机制。在目标2中，我们将评估增强KISS1R信号对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学、实验室、放射学和人口统计学特征相关。此外，还将研究肝KISS1R在NAFLD/NASH肝活检中的表达和定位。了解这些知识很重要，因为它将阐明利用KISS1R信号通路作为开发减少NAFLD和NASH的新药理学方法的潜在途径。