This application addresses broad Challenge Area (11): Regenerative Medicine and specific Challenge Topic 11-AA-102: Roles of Cellular Organelles and the Cytoskeleton in Alcohol-induced Organ Damage. Alcohol abuse and alcohol-induced liver disease are a major health concern in the US and worldwide. Alcoholic fatty liver disease (AFLD) is marked by the aberrant accumulation of intracellular fatty acids in hepatocytes and can progress to hepatitis, fibrosis, cirrhosis, and liver failure. Steatosis, the accumulation of fat in hepatocytes, is the reversible initial step of AFLD. As such, it is a prime target for therapeutic intervention to block AFLD progression. Intracellular lipids are stored in hepatocytes in lipid droplets, dynamic organelles that accumulate in excess in steatosis. However, the formation, regulation, and metabolism of lipid droplets are poorly understood. This proposal will focus on defining the mechanisms of lipid droplet trafficking, their interaction with other central intracellular organelles and how these processes are altered under conditions of ethanol exposure. Our central hypothesis is that chronic ethanol exposure alters the normal vesicle trafficking between lipid droplets and other membrane organelles in the hepatocyte, leading to fatty liver. The endoplasmic reticulum (ER), Golgi apparatus, and endosomal compartments have all been linked to lipid droplets. Two different laboratories expert in alcohol induced liver damage and hepatocellular membrane-cytoskeletal dynamics will work in synergy to determine the functions of each of these organelles in regulating lipid droplet formation and metabolism under normal conditions and following ethanol exposure to mediate the progression of AFLD.

Public Health Relevance

The goal of this proposal is to examine how impairments and alterations in trafficking and targeting of lipid droplets (LD) to specific organelles influences LD accumulation in steatosis and contributes to alcohol-induced fatty liver disease (AFLD). We hypothesize that chronic ethanol exposure alters the normal vesicle trafficking between lipid droplets and Golgi, endosomes, and endoplasmic reticulum, leading to fatty liver and subsequently hepatocellular damage. Successful completion of these studies will provide information which could lead to therapeutic strategies that might reduce the severity of steatosis and block the further progression to steatohepatitis, fibrosis and cirrhosis

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
1RC1AA019032-01
Application #
7819361
Study Section
Special Emphasis Panel (ZRG1-DKUS-A (58))
Program Officer
Radaeva, Svetlana
Project Start
2009-09-30
Project End
2011-08-31
Budget Start
2009-09-30
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$499,999
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Natarajan, Sathish Kumar; Rasineni, Karuna; Ganesan, Murali et al. (2017) Structure, Function and Metabolism of Hepatic and Adipose Tissue Lipid Droplets: Implications in Alcoholic Liver Disease. Curr Mol Pharmacol 10:237-248
Li, Zhipeng; Schulze, Ryan J; Weller, Shaun G et al. (2016) A novel Rab10-EHBP1-EHD2 complex essential for the autophagic engulfment of lipid droplets. Sci Adv 2:e1601470
Schroeder, Barbara; Schulze, Ryan J; Weller, Shaun G et al. (2015) The small GTPase Rab7 as a central regulator of hepatocellular lipophagy. Hepatology 61:1896-907
Rasineni, Karuna; McVicker, Benita L; Tuma, Dean J et al. (2014) Rab GTPases associate with isolated lipid droplets (LDs) and show altered content after ethanol administration: potential role in alcohol-impaired LD metabolism. Alcohol Clin Exp Res 38:327-35
Schulze, Ryan J; Weller, Shaun G; Schroeder, Barbara et al. (2013) Lipid droplet breakdown requires dynamin 2 for vesiculation of autolysosomal tubules in hepatocytes. J Cell Biol 203:315-26
McVicker, Benita L; Rasineni, Karuna; Tuma, Dean J et al. (2012) Lipid droplet accumulation and impaired fat efflux in polarized hepatic cells: consequences of ethanol metabolism. Int J Hepatol 2012:978136
McNiven, Mark A; Casey, Carol A (2011) Alcohol and lipid traffic don't mix. Hepatology 53:1073-5