Targeting Shc to reduce inflammation and fibrosis in the aging liver

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Aging increases the prevalence and severity of liver disease, and this more severe, fibrotic form of liver disease is significantly increasing mortality in the elderly. Non-alcoholic steatohepatitis (NASH) is rapidly becoming the most common liver disease and presents with advanced fibrosis or cirrhosis in older patients. There is no approved medical therapy for NASH. The mechanistic factors that underlie the rising risk for fibrosis and death are not understood, although redox, inflammatory and mitochondrial factors have been implicated. We demonstrate for the first time that NASH in more common and severe in aged mice, and that Src homology 2 domain containing (Shc) protein and its newly identified ROS-producing partner NADPH oxidase 2 are induced. We propose a novel paradigm that aging accelerates NASH leading to cirrhosis; and the Shc proteins play in this process an essential role. Thus to study how longevity and redox pathways are integrated we hypothesized that during aging the combined effects of increased pShc46 and 52 activities are central to elicit an enhanced pro-oxidant, inflammatory and fibrogenic activity in NASH. To address this hypothesis we will focus on: 1) The molecular mechanism of Shc-p47phox binding, trafficking to the membrane, and the formation of the active NOX2 enzyme in hepatocytes; 2) The role of p46Shc in modulating palmitate oxidation, toxicity, and insulin resistance in hepatocytes; and 3) Determining the in vivo effects of Shc signaling on inflammation, insulin resistance, steatosis, oxidative injury and fibrosis in conditional hepatocyte-specific ShcKO mice (young vs. old) and DN models on NASH diets. We will also study the effects of Shc inhibition by idebenone on NASH in young and old mice both in preventive and treatment protocols. These studies will help in understanding age- specific profibrogenic pathways and set the frame for developing effective treatment options for NASH in the elderly.