Alcohol-induced liver damage is a common liver disease that is due in part to dysregulated lipid metabolism and inflammation. Alcoholic liver disease (ALD) progresses through four pathological stages: steatosis, steatohepatitis, fibrosis and cirrhosis. There is a strong link between the severity of lipid accumulation and the development of liver toxicity. Increased hepatic lipid accumulation enhances the ability of xenobiotics and endotoxins produced in the gut to potentiate alcoholic hepatitis and fibrosis, likely by increased inflammatory signaling, which is dependent on Kupffer cell/hepatocyte interactions and other immune cells. Peroxisome proliferator-activated receptor-a (PPARa) has a central role in regulating fatty acid catabolism in liver. Given the significance of lipid accumulation in the etiology of ALD, it is not surprising that Ppara-null mice exhibit exacerbated ALD as compared to mice expressing a functional PPARa. In contrast to PPARa that regulates lipid catabolism, it was recently shown that PPAR?/d also modulates hepatic lipid metabolism by inhibiting hepatic lipogenesis by inducing expression of insulin-induced gene-1 (Insig-1), an endoplasmic reticulum protein that inhibits SREBP activation. Preliminary data will establish that PPAR?/d can protect against liver damage by toxins, supporting the hypothesis that PPAR?/d will also protect against ALD, an idea that has not been examined to date. Coupled with strong evidence that PPARa and PPAR?/d have potent anti- inflammatory activities, the focus of this application is on elucidating the mechanisms by which PPARa and PPAR?/d regulate hepatic lipid accumulation and hepatic inflammation, two known pathways critical in mediating ALD.
Specific aim 1 will use the Ppara-null and Pparb/d-null mouse models to distinguish between the suitability of targeting these receptors to inhibit early and/or pre-existing ALD and the mechanisms by which PPARa and PPAR?/d modulate hepatic alcohol-induced toxicity. Evaluation of PPAR agonism in these models will be evaluated by comparing gene expression and targeted metabolomic profiles with liver pathology to mechanistically delineate how PPARa and PPAR?/d regulate hepatic lipid metabolism in an ALD model.
Specific aim 2 will use innovative and novel transgenic mouse models to determine if inflammation modulates PPAR-dependent hepatic lipid accumulation in promoting ALD and to distinguish between somatic cell- mediated inflammation (e.g. hepatocyte) versus immune cell-mediated inflammation (e.g,. Kupffer cell, neutrophils, lymphocytes). Results from this application will determine whether combining ligand activation of PPARa and PPAR?/d and/or inhibition of p38-dependent inflammation will improve approaches to prevent or treat ALD with a solid mechanistic rationale. This application combines the unique expertise and experience of Dr. Albert J. Fornace's laboratory (Georgetown University) and Dr. Jeffrey M. Peters (Penn State University) to define the PPAR regulatory and inflammation-dependent inducing mechanisms that are essential for ALD.

Public Health Relevance

Alcohol-induced liver damage is a common liver disease with important health and socioeconomic consequences that is due in part to dysregulated lipid metabolism and inflammation. This application combines the unique expertise and experience of Dr. Albert J. Fornace's laboratory (Georgetown University) and Dr. Jeffrey M. Peters (Penn State University) to define lipid metabolism regulatory and inflammation-dependent inducing mechanisms that are essential for alcoholic liver disease. Results will improve approaches to prevent or treat alcoholic liver disease with a solid mechanistic rationale.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA018863-04
Application #
8316435
Study Section
Special Emphasis Panel (ZAA1-JJ (06))
Program Officer
Radaeva, Svetlana
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$413,936
Indirect Cost
$77,652
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Koga, Takayuki; Yao, Pei-Li; Goudarzi, Maryam et al. (2016) Regulation of Cytochrome P450 2B10 (CYP2B10) Expression in Liver by Peroxisome Proliferator-activated Receptor-β/δ Modulation of SP1 Promoter Occupancy. J Biol Chem 291:25255-25263
Moffat, Ivy; Chepelev, Nikolai L; Labib, Sarah et al. (2015) Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water. Crit Rev Toxicol 45:1-43
Li, Heng-Hong; Hyduke, Daniel R; Chen, Renxiang et al. (2015) Development of a toxicogenomics signature for genotoxicity using a dose-optimization and informatics strategy in human cells. Environ Mol Mutagen 56:505-19
Peters, Jeffrey M; Yao, Pei-Li; Gonzalez, Frank J (2015) Targeting Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) for Cancer Chemoprevention. Curr Pharmacol Rep 1:121-128
Li, Heng-Hong; Tyburski, John B; Wang, Yi-Wen et al. (2014) Modulation of fatty acid and bile acid metabolism by peroxisome proliferator-activated receptor α protects against alcoholic liver disease. Alcohol Clin Exp Res 38:1520-31
Zhu, Bokai; Ferry, Christina H; Markell, Lauren K et al. (2014) The nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) promotes oncogene-induced cellular senescence through repression of endoplasmic reticulum stress. J Biol Chem 289:20102-19
Zhu, B; Ferry, C H; Blazanin, N et al. (2014) PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling. Oncogene 33:5348-59
Yao, Pei-Li; Morales, Jose L; Zhu, Bokai et al. (2014) Activation of peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) inhibits human breast cancer cell line tumorigenicity. Mol Cancer Ther 13:1008-17
Li, Heng-Hong; Doiron, Kathryn; Patterson, Andrew D et al. (2013) Identification of serum insulin-like growth factor binding protein 1 as diagnostic biomarker for early-stage alcohol-induced liver disease. J Transl Med 11:266
Goudarzi, Maryam; Koga, Takayuki; Khozoie, Combiz et al. (2013) PPARβ/δ modulates ethanol-induced hepatic effects by decreasing pyridoxal kinase activity. Toxicology 311:87-98

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