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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020709-04
Application #
8705327
Study Section
Special Emphasis Panel (ZAA1-JJ (01))
Program Officer
Radaeva, Svetlana
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$369,933
Indirect Cost
$151,683
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Lade, Abigale; Noon, Luke A; Friedman, Scott L (2014) Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis, hepatic fibrosis, and cancer. Curr Opin Oncol 26:100-7
Jiao, Jingjing; Dragomir, Ana-Cristina; Kocabayoglu, Peri et al. (2014) Central role of conventional dendritic cells in regulation of bone marrow release and survival of neutrophils. J Immunol 192:3374-82
Fabre, Thomas; Kared, Hassen; Friedman, Scott L et al. (2014) IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-? receptor on hepatic stellate cells in a JNK-dependent manner. J Immunol 193:3925-33
Lee, Youngmin A; Friedman, Scott L (2014) Reversal, maintenance or progression: what happens to the liver after a virologic cure of hepatitis C? Antiviral Res 107:23-30
Vacaru, Ana M; Unlu, Gokhan; Spitzner, Marie et al. (2014) In vivo cell biology in zebrafish - providing insights into vertebrate development and disease. J Cell Sci 127:485-95
Hernandez-Gea, Virginia; Toffanin, Sara; Friedman, Scott L et al. (2013) Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144:512-27
Czaja, Mark J; Ding, Wen-Xing; Donohue Jr, Terrence M et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9:1131-58
Friedman, Scott L (2013) Liver fibrosis in 2012: Convergent pathways that cause hepatic fibrosis in NASH. Nat Rev Gastroenterol Hepatol 10:71-2
Hernandez-Gea, Virginia; Hilscher, Moira; Rozenfeld, Raphael et al. (2013) Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J Hepatol 59:98-104
Friedman, Scott L; Sheppard, Dean; Duffield, Jeremy S et al. (2013) Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 5:167sr1

Showing the most recent 10 out of 11 publications