Tumor necrosis factor-a- (TNF) and mitochondrial GSH (mGSH) are two factors that modulate alcohol-induced liver injury and progression of alcoholic liver disease (ALD). The overall goal of this proprosal is to identify the signaling intermediates generated by TNF that target mitochondria and the role of mitochondrial cholesterol and lipid composition on the regulation of mGSH and mitochondrial permeability transition (MPT).
Specific aims : 1. Role of acidic sphingomyelinase (ASMase) on alcohol-mediated hepatocellular injury. Ceramide functions as a lipid death effector through its interaction with mitochondria. Thus, we will examine the specific role of ASMase on the sensitization of the liver to alcohol feeding vs. known contributors of TNF cytotoxicity (Bid, cathepsin B). Rats with inactive endogenous ASMase and ASMase deficient mice will be fed ethanol chronically evaluating the sensitization of the liver to alcohol-induced liver injury. 2. Contribution of ganglioside GD3 to the progression of ALD. Ganglioside GD3 (GD3), a sialic-acid containing glycosphingolipid synthesized from ceramide within the Golgi network, interacts with mitochondria by an actin cytoskeleton vesicular trafficking. The intracellular trafficking of GD3 will be characterized in hepatocytes from alcohol-fed rats and its role in alcohol liver injury will be assessed in GD3 synthase knockout mice. 3. Regulation of mGSH by cholesterol: intramitochondrial cholesterol trafficking and role of peripheral benzodiazepine receptor (PBR). The mGSH arises by the mGSH carrier whose activity is sensitive to altered membrane fluidity due to increased cholesterol deposition. We will determine the temporal relationship between incrased mitochondrial cholesterol and mGSH depletion by alcohol feeding. In addition, we will examine the regulation of cholesterol by alcohol, the role of hydroxymethylglutaryI-CoA reductse and the collaboration of PBR in the intramitochondrial trafficking of cholesterol. 4. MPT: role of cardiolipin and MPT components. MPT is key in TNF-mediated hepatocellular injury and alcohol has been shown to potentiate MPT. Since cardiolipin, an exclusive mitochondrial phospholipid, has been recently suggested to interact with proapoptotic Bcl-2 family members that induce MPT,we will examine the role of cardiolipin vs MPT components reconstituted liposomes in MPT regulation in mitochondria and mitoplasts isolated from alcohol-fed rats.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA011999-07
Application #
7062902
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
7
Fiscal Year
2005
Total Cost
$141,514
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Eguchi, Akiko; Lazaro, Raul G; Wang, Jiaohong et al. (2017) Extracellular vesicles released by hepatocytes from gastric infusion model of alcoholic liver disease contain a MicroRNA barcode that can be detected in blood. Hepatology 65:475-490
Vollmann, Elisabeth H; Cao, Lizhi; Amatucci, Aldo et al. (2017) Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing. Mol Ther Nucleic Acids 7:314-323
Jang, Jung Eun; Park, Han-Sol; Yoo, Hyun Ju et al. (2017) Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice. Hepatology 66:416-431
Khanova, Elena; Wu, Raymond; Wang, Wen et al. (2017) Pyroptosis by Caspase11/4-Gasdermin-D Pathway in Alcoholic Hepatitis. Hepatology :
Arenas, Fabian; Garcia-Ruiz, Carmen; Fernandez-Checa, Jose C (2017) Intracellular Cholesterol Trafficking and Impact in Neurodegeneration. Front Mol Neurosci 10:382
García-Ruiz, Carmen; Ribas, Vicente; Baulies, Anna et al. (2017) Mitochondrial Cholesterol and the Paradox in Cell Death. Handb Exp Pharmacol 240:189-210
McDaniel, Kelly; Huang, Li; Sato, Keisaku et al. (2017) The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury. J Biol Chem 292:11336-11347
Koyama, Yukinori; Wang, Ping; Liang, Shuang et al. (2017) Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J Clin Invest 127:1254-1270
Setiawan, Veronica Wendy; Pandol, Stephen J; Porcel, Jacqueline et al. (2017) Dietary Factors Reduce Risk of Acute Pancreatitis in a Large Multiethnic Cohort. Clin Gastroenterol Hepatol 15:257-265.e3
Sheth, Sunil G; Conwell, Darwin L; Whitcomb, David C et al. (2017) Academic Pancreas Centers of Excellence: Guidance from a multidisciplinary chronic pancreatitis working group at PancreasFest. Pancreatology 17:419-430

Showing the most recent 10 out of 402 publications