ALD is one of the most common causes of chronic liver disease in the United States, and many other countries. ALD represents a wide spectrum of liver damage ranging from alcoholic steatosis, to alcoholic steatohepatitis (ASH), to cirrhosis. ASH represents a stage within the spectrum of ALD that is characterized by the accumulation of lipid stores in the liver (steatosis) along with inflammation and different degrees of scarring or fibrosis (8). ASH is potentially serious condition, as patients with ASH are at particular risk for disease progression to cirrhosis and its complications including portal hypertension, liver failure and hepatocellular carcinoma (4, 9). Chronic ethanol consumption alters liver mitochondria structure as well as function (2-5), and recent work suggests that this chronic ethanol-related disturbance in mitochondria health might also be responsible for an increased production of ROS, a central abnormality responsible for liver injury and disease progression in ALD (6-12). The central question extant is what events link excess alcohol consumption to mitochondrial dysfunction. Small increases in mitochondrial ROS production may lead to subsequent severe derangement and massive ROS production, membrane potential collapse, swelling and cytochrome c release (13). These events proceed, and are responsible for, apoptotic cell death. The peroxide function of phospholipid (hydro)peroxides are chemically reactive and can disintegrate to form a variety of fragmented phospholipids with varied sn-2 residues. Phospholipid hydroperoxides also are the source of free fatty acid hydroperoxides, and so are early markers of oxidative stress. Some of these phospholipid oxidation products potently disrupt mitochondrial structure with cytochrome c release in in vitro assays. These are more than markers of oxidation because we find (1) that fragmented phospholipids readily enter cells, damage mitochondria in situ, and initiate the intrinsic apoptotic cascade.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory Grants (P20)
Project #
5P20AA017837-05
Application #
8529403
Study Section
Special Emphasis Panel (ZAA1-BB)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$29,132
Indirect Cost
$10,576
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Barnes, Mark A; Roychowdhury, Sanjoy; Nagy, Laura E (2014) Innate immunity and cell death in alcoholic liver disease: role of cytochrome P4502E1. Redox Biol 2:929-35
Bakhautdin, Bakytzhan; Das, Dola; Mandal, Palash et al. (2014) Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice. J Hepatol 61:1029-37
Thapaliya, Samjhana; Runkana, Ashok; McMullen, Megan R et al. (2014) Alcohol-induced autophagy contributes to loss in skeletal muscle mass. Autophagy 10:677-90
Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M (2014) Chronic ethanol ingestion induces oxidative kidney injury through taurine-inhibitable inflammation. Free Radic Biol Med 69:403-16
Roychowdhury, Sanjoy; Chiang, Dian J; McMullen, Megan R et al. (2014) Moderate, chronic ethanol feeding exacerbates carbon-tetrachloride-induced hepatic fibrosis via hepatocyte-specific hypoxia inducible factor 1? Pharmacol Res Perspect 2:e00061
Cresci, Gail A; Bush, Katelyn; Nagy, Laura E (2014) Tributyrin supplementation protects mice from acute ethanol-induced gut injury. Alcohol Clin Exp Res 38:1489-501
Barnes, Mark A; McMullen, Megan R; Roychowdhury, Sanjoy et al. (2013) Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis. Hepatology 57:1980-91
Dixon, Laura J; Flask, Chris A; Papouchado, Bettina G et al. (2013) Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis. PLoS One 8:e56100
Dixon, Laura J; Barnes, Mark; Tang, Hui et al. (2013) Kupffer cells in the liver. Compr Physiol 3:785-97
Roychowdhury, Sanjoy; McMullen, Megan R; Pisano, Sorana G et al. (2013) Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57:1773-83

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