Alcoholic steatohepatitis is the initial stage of alcoholic liver disease (ALD) and a major risk factor for advanced liver injuries, including fibrosis/cirrhosis, hepatocellular carcinoma and liver failure. Despite a large body of evidence suggesting that the early stage of ALD, alcoholic steatohepatitis, is driven by organ crosstalk, lack of knowledge on the inter-organ crosstalk endocrine coordinators and their roles in alcoholic steatohepatitis has hampered the progress of ALD research. This proposal is a competing continuation of the grant, titled ?Ethanol Regulation of Adiponectin and It's Signaling. Our group has recently investigated the underlying mechanisms of ethanol-mediated impairment of adiponectin signaling by identifying a new target of ethanol action, fibroblast growth factor (FGF) 15 (human homolog, FGF19), an ileum-derived hormone. We have found that dysregulated adiponectin-FGF15/19 axis and impaired adiponectin-FGF15/19 signaling are associated with alcoholic steatohepatitis in rodents and humans. More importantly, adiponectin-FGF15/19 axis confers protection against ethanol-induced liver damage via fine-tuning the adipose-intestine-liver crosstalk. Therefore, this current renewal proposal will examine a novel and exciting central hypothesis that adiponectin-FGF15/19 axis plays a pivotal role in the development of alcoholic steatohepatitis. This central hypothesis will be pursued through three complementary aims.
In Aim 1, we will investigate the role of adiponectin-FGF15/19 axis in the development of alcoholic steatohepatitis in mice.
In Aim 2, we will dissect the mechanisms through which ethanol impairs adiponectin-FGF15/19 signaling in cultured hepatocytes and in mouse livers.
In Aim 3, we will investigate the underlying mechanisms by which ethanol down-regulates FGF15/19 in cultured intestinal cells and in mouse ileum. We will utilize molecular, cellular, and biochemical approaches with cell culture and in genetically or adenoviral modified mouse models to dissect the molecular and cellular events mediating the effects of ethanol on adiponectin-FGF15/19 axis and it's signaling. Pharmacological or nutritional reagents designed to enhancing or optimizing the adiponectin-FGF15/19 axis may serve novel therapeutic strategies in the management and treatment of human alcoholic steatohepatitis.
Endocrine adiponectin-FGF15/19 axis is a pivotal adipose-gut-liver coordinator involved in the development and progression of alcoholic steatohepatitis. This renewal application will study the mechanisms by which ethanol dysregulates adiponectin-FGF15/19 axis and impairs its signaling. The proposed studies will lay the groundwork for the development of novel therapeutic strategies in the management and treatment of human alcoholic steatohepatitis.
Showing the most recent 10 out of 28 publications
