Progressive hepatic fibrosis and cirrhosis leading to end-stage liver disease are major consequences of chronic alcohol abuse that cost thousands of lives, and hundreds of millions of dollars in health care costs. Despite the clear link between alcohol, fibrosis and end-stage liver disease, there are no approved antifibrotic therapies that can delay disease progression or forestall complications of fibrosis, and thus progress is urgently needed. The hepatic stellate cell (HSC), following activation during alcoholic liver injury, plays a central role in the development of fibrosis. Our long-term goal is to understand how HSC activation is stimulated in response to alcohol;progress will lead to novel, targeted interventions for alcoholic liver disease. A study published by others describing loss of lipid droplets as a feature of autophagy sparked our idea that autophagy is a component of HSC activation. Autophagy is a highly regulated cellular response that has evolved to maintain energy homeostasis during cellular stress or enhanced metabolic demand, and its features remarkably parallel those of HSC activation. The objective of this project, which is the next step towards our long-term goal, is to characterize the contribution of autophagy to HSC activation in alcoholic liver injury. Our central hypothesis, therefore, is that autophagy is a critical and necessary component of HSC activation in alcoholic fibrosis. We will test our central hypothesis through the following interrelated Specific Aims: 1. Define stimuli associated with alcoholic liver injury that provoke autophagy in HSCs, by using ethanol-specific culture models of HSC activation in which autophagy will be documented by: Western blot to detect conversion of LC3-I protein to LC3-II, ultrastructure, and reduced lipid content. 2. Determine which features of autophagy during HSC activation in vivo are alcohol-dependent by characterizing the response to siRNA knockdown of Atg7 or Atg5 in HSCs from ethanol-fed mice, and define autophagy-regulated pathways by quantitative PCR and Western for known activation markers, and exon arrays for novel targets. 3. Establish the dependence of alcohol-related HSC activation on autophagy in vivo by blocking autophagy in alcohol-fed mice. These studies should uncover fundamental new pathways of stellate cell activation specifically related to alcohol's effects in the liver, leading to innovative treatment approaches for patients with alcoholic liver disease.
Chronic alcoholic liver disease leads to scarring, or fibrosis, of the liver, and is a large public health challenge, affecting millions of patients. We propose to study a specialized pathway called autophagy, that drives activation of hepatic stellate cells in liver to make scar in alcoholic fibrosis. New insights expected to emerge from these novel studies could significantly advance our understanding of how to block scar formation in alcoholic liver disease, accelerate liver repair, and prevent the end-stage of liver disease called cirrhosis, thereby improving the lives of patients throughout the world.
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|Friedman, Scott L; Sheppard, Dean; Duffield, Jeremy S et al. (2013) Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 5:167sr1|
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