Hepatic kisspeptin receptor signaling in nonalcoholic fatty liver

项目摘要 在美国，肥胖症的患病率不断增加，这与代谢合并症有关 如2型糖尿病（T2 D）和非酒精性脂肪肝（NAFLD）， 特征是在很少喝酒或不喝酒的人中肝脏脂肪过度积累。虽然 有许多药物批准用于T2 D，没有药物批准用于NAFLD， 现在是慢性肝病的主要原因，也是肝脏疾病增长最快的原因。 移植NAFLD的第一阶段是脂肪变性（脂肪肝），其可以进展为非脂肪肝。 酒精性脂肪性肝炎（NASH），其中肝脏中的脂肪积累与 炎症和疤痕。随着肝细胞逐渐被疤痕组织所取代，肝脏停止 功能正常。肝脏产生一种称为kisspeptin（KP）的肽，在肝脏中循环。 血KP结合一种称为kisspeptin 1受体（KISS 1 R）的蛋白质。虽然KISS 1 R 在肝脏中表达，其功能尚不清楚。我们新的试验数据显示，KP/KISS 1 R 信号传导可以抑制肝脏中的脂肪积累。使用转基因小鼠模型， 血浆来源于NAFLD患者，拟议的工作将确定KISS 1 R是否 信号传导阻止NAFLD的发展和潜在机制。在目标1中，我们 研究肝脏KISS 1 R信号传导抑制脂肪生成的机制。在目标2中， 将确定增加KISS 1 R信号传导对NASH和纤维化发展的影响。 总的来说，这些临床转化的发现可能会将KISS 1 R确定为一种新的靶点， 预防NAFLD的发展。

PROJECT SUMMARY The increasing prevalence of obesity in the U.S.A. is associated with metabolic comorbidities such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), a disease characterized by excess liver fat accumulation in people who drink little to no alcohol. Although there are many medications approved for T2D, no medications are approved for NAFLD, which is now the leading cause of chronic liver disease and fastest-growing reason for liver transplantation. The first stage of NAFLD is steatosis (fatty liver), that can progress to non- alcoholic steatohepatitis (NASH) where fat accumulation in the liver is associated with inflammation and scarring. As the liver cells are gradually replaced by scar tissue, the liver stops functioning properly. The liver produces a peptide known as kisspeptin (KP) that circulates in the blood. KP binds a protein known as the kisspeptin 1 receptor (KISS1R). Although KISS1R is expressed in the liver, its function is unknown. Our new pilot data has revealed that KP/KISS1R signaling can inhibit fat accumulation in the liver. Using genetically modified mouse models and plasma derived from NAFLD patients, the proposed work will determine whether KISS1R signaling prevents the development of NAFLD and the underlying mechanisms. In Aim 1, we will investigate the mechanisms by which hepatic KISS1R signaling inhibits lipogenesis. In Aim 2, we will determine the effect of increasing KISS1R signaling on the development of NASH and fibrosis. Collectively, these clinically translational findings may identify KISS1R as a novel target for the preventive treatment against the development of NAFLD.