Stat5b as a potential therapeutic target to treat NASH

ANDRE SARMENTO-CABRAL; PAPASANI V. SUBBAIAH; MERCEDES DEL RIO-MERENO; JOSE CORDOBA-CHACON; BELEN BRIE; RHONDA D. KINEMAN

Chicago

Jornada; Faculty Retreat of the Division of Endocrinology, Diabetes and Metabolism; 2018

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of excess fat accumulation in the liver (steatosis) without or with inflammation/fibrosis (non-alcoholic steatohepatitis - NASH). NAFLD is commonly observed in obesity and type 2 diabetes, but is also observed in non-obese patients associated with cardiovascular disease. To date, there are no proven medical therapies to reverse NAFLD. In order to develop effective treatments, it is critical to understand the basic mechanisms controlling hepatic fat accumulation and associated liver damage. Since both clinical and experimental studies demonstrate hepatic growth hormone (GH)-signaling is reduced in NAFLD and increasing GH can reduce NAFLD both in humans and mice, our recent work has focused on determining how GH mediates these effects. We have used unique mouse models with adult-onset hepatocyte-specific GH receptor knockdown (aHepGHRkd) and demonstrated GH signaling controls steatosis by suppressing de novo lipogenesis (DNL), an action of GH not previously appreciated. Importantly, in chow-fed mice, aHepGHRkd sustains hepatic DNL/steatosis with age, and is associated with elevated plasma alanine aminotransferase levels, hepatocyte ballooning, inflammation and mild fibrosis; all hallmarks of early-stage NASH. Also, aHepGHRkd exacerbates steatosis induced by a high carbohydrate/high fat diet and leads sex dependent early morbidity. Additional preliminary data, coupled with published reports, led us to formulate the HYPOTHESIS: GH directly controls hepatocyte DNL via GHR/Stat5b-mediated regulation of glycolysis, to protect the liver from injury. To begin to test this hypothesis we developed an adenoviral-associated vector that expresses a constitutively active (CA) Stat5b under the control of the thyroid binding globulin promoter (AAV-TBGp-Stat5bCA), which exclusively targets hepatocytes. Preliminary data indicate that enhancing hepatocyte Stat5b activity reduces steatosis and endpoints of liver injury in mice with aHepGHRkd, as well as mice with diet-induced steatosis. These initial studies present the exciting possibility that hepatocyte Stat5b could represent a drug target to treat NASH.