BLRD Research Career Scientist Award Application

Jesse Brown Va Medical Center, Chicago IL

Investigators

Linked publications & trials

Abstract

The overarching theme of my current research is to understand how growth hormone (GH) and insulin-like growth factor I (IGF1) regulate adult metabolic function and how dysregulation of GH/IGF1 production and signaling contributes to the progression of metabolic disease, as well as related tissue injury and repair. A major focus of my work is to understand the etiology of non-alcoholic fatty liver disease (NAFLD). 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, where all diseases are more prevalent in Veterans, compared to the general population. NASH increases the risk of developing liver cancer, and is now recognized as the leading cause for liver transplantation. Dietary fatty acids (FA) and FA derived from adipose tissue lipolysis, due to systemic insulin resistance, are major contributors to NAFLD. In addition, enhanced hepatic de novo lipogenesis (DNL) contributes to NAFLD. Clinical and experimental studies show NAFLD is associated with reduced GH-signaling (reflected by low plasma GH and hepatic GH resistance, leading to low IGF1 levels). The reduction in GH-signaling may exacerbate NAFLD, based on studies showing SNPs within the GH / GH receptor (GHR) /JAK2 / Stat5 signaling pathway are associated with NAFLD. Also, increasing GH can reduce NAFLD in both humans and mice. We have reported that adult-onset loss of hepatocyte GH signaling (aHepGHRkd; GHRfl/fl mice treated with an adeno-associated viral vector expressing thyroxine binding globulin promoter driven Cre [AAV8-TBGp-Cre]) led to the rapid development of steatosis, associated with an increase in DNL (Cordoba-Chacon et al., Diabetes 2015). Of translational relevance, hepatic DNL/steatosis after aHepGHRkd is sustained with age and associated with hepatocyte ballooning, inflammation and fibrosis (hallmarks of NASH; Cordoba-Chacon et al., Endocrinology 2018). Studies outlined in my current R01 take a multi-level approach to define the biochemical/molecular mechanisms by which hepatocyte GH-signaling directly controls glycolysis-driven DNL and steatosis, by manipulating hepatocyte GH signaling in mice by hepatocyte-specific, AAV-vector delivery of transgenes within the GH-signaling pathway then assessing; gene and protein expression of enzymes in glycolytic and lipogenic pathways, fatty acid composition by GC/MS, glycolytic flux and TCA cycle intermediates under hyperinsulinemic:hyperglycemic clamps, using stable isotope tracers. Studies outlined in my current BL&RD VA Merit are focused how the reduction in hepatocyte GH signaling contributes to diet-induced NASH and how reconstitution of the GHR signaling pathway (specifically Stat5b activity and/or IGF1 using AAV vector delivery) may prevent and/or reverse steatosis and liver injury. To date we have exciting preliminary data suggesting, hepatocyte GH-signaling works independently of Stat5b/IGF1 to suppress hepatic DNL, while Stat5b is critical to protect the liver from diet-induced injury. These protective effects may extend to other types of liver injury including those induced by environmental toxins (focus of CACHET pilot award). In addition to assessing the role of GH/IGF1 in protecting the liver from injury, in collaboration with Timothy Koh, PhD (UIC, wound healing expert) we are exploring the role of IGF1 in regulating diabetic wound healing. These studies are funded by a RR&D VA Merit and examine the basic mechanisms of wound healing in mouse models of insulin-resistance (diet-induced) and diabetes (db/db) with or without hepatic IGF1 production. Studies will also examine if low-intensity vibration patches (developed and optimized by Onur Bilgen PhD, Rutgers) can speed wound healing via enhanced IGF1 production/actions. Taken together, these basic studies will help to identify unique targets that can be used to develop treatment strategies, in order to prevent the deleterious consequences of obesity/diabetes, which are commonly found in the Veteran population.