Hepatic kisspeptin receptor signaling in nonalcoholic fatty liver

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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.