Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases that can lead to steatohepatitis (NASH) and cirrhosis. According to current concepts, disease progression from steatosis occurs after multiple hits but the factors implicated in this are poorly understood. The presentation of NASH is clinically heterogeneous, and many patients especially those with diabetes, present with already advanced steatohepatitis and fibrosis. Type II diabetes mellitus (DM) is a major risk factor for necroinflammatory disease however; the detailed mechanistic links between diabetes and the proinflammatory and fibrogenic activity in the liver have not been defined. In this application we propose a novel paradigm that in diabetics NASH is initiated as an aggressive inflammatory disorder that results in fibrosis. DM leads to the accumulation of advanced glycation end-products (AGEs) as a result of a non-enzymatic glycation of serum proteins. The pathogenic role of AGEs in NASH are not defined thus we seek to identify the cellular targets of AGEs in the liver, the receptors and signaling pathways responsible for oxidative, inflammatory and fibrogenic injury. Our main goal is to provide mechanistic insights on the central role of AGEs initiating immunogenic cell death of hepatocytes, and subsequent inflammatory and fibrogenic events. We will focus on 1) Determining how the exposure of hepatocytes to AGEs results in the induction of stress signaling leading to immunogenic cell death and exposure of find-me signals for phagocytes, 2) Studying RAGE-mediated tethering and engulfment (efferocytosis) of apoptotic hepatocytes priming macrophages for the induction of inflammatory pathways and fibrosis.; 3) To define the in vivo effects of AGEs/RAGE on inflammation, oxidative injury, fibrosis steatosis, and insulin resistance in NASH in in vivo models. These studies will significantly enhance our understanding the proinflammatory effects of diabetes in NASH, the cell-specific actions of AGE/RAGE signaling thus highlighting future avenues in developing effective treatment options.
Nonalcoholic steatohepatitis (NASH) is becoming the most common of chronic liver diseases and a major cause of liver related morbidity and mortality. In a few years NASH will be the leading etiologies for liver transplantation, and since there is no rational therapeutics available, it is extremely important to better understand the pathogenesis of inflammation and fibrosis in this disease. Diabetes is a major risk factor for disease progression. This proposal is aimed at elucidating the role of advanced glycation end products that accumulate in diabetes and their receptor (RAGE) in pro-oxidant and proinflammatory liver injury that drive progression of NASH towards fibrosis and cirrhosis. Based on the data new treatment strategies will be designed to treat nonalcoholic steatoheaptitis.
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