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United States Department of Agriculture

Agricultural Research Service


Location: Arkansas Children's Nutrition Center

Title: Increased accumulation of 4-hydroxynonenal adducts in male GSTA4/PPAR alpha double knockout mice enhances injury during early stages of alcoholic liver disease

item Mercer, Kelly
item Sharma, Neha
item Shearn, C
item Vantrease, Jamie
item Bozzola, C
item Albano, E
item Badger, Thomas
item Ronis, Martin
item Petersen, Denis

Submitted to: Hepatology
Publication Type: Abstract Only
Publication Acceptance Date: 9/15/2013
Publication Date: 12/15/2013
Citation: Mercer, K.E., Sharma, N.E., Shearn, C.T., Vantrease, J., Bozzola, C., Albano, E., Badger, T.M., Ronis, M.J., Petersen, D.R. 2013. Increased accumulation of 4-hydroxynonenal adducts in male GSTA4/PPAR alpha double knockout mice enhances injury during early stages of alcoholic liver disease [abstract]. Hepatology. 58(S1): #717. p92A–207A. doi: 10.1002/hep.26726.

Interpretive Summary:

Technical Abstract: Hepatic lipid peroxidation and accumulation of aldehyde-adducted proteins occur early in alcohol-mediated injury and are postulated to mediate the subsequent pro-inflammatory and fibrotic responses observed in alcoholic liver disease. To test the significance of lipid peroxidation formation in the development of early-stage liver injury, we fed a Lieber-DeCarli ethanol (EtOH) liquid diet to male 129/SvJ glutathione S-transferase A4 knockout mice (GST'4-/-) mice for 40 d. These mice lack the ability to metabolize lipid peroxidation products, particularly 4-hydroxynonenal (4-HNE). At sacrifice, we observed marked increases in malondialdehyde (MDA) and 4-HNE adducts in liver sections, increased lipid accumulation, and mRNA expression of molecular markers of inflammation (TNF alpha, CD14) and fibrosis (ColA1, alpha'SMA) in the EtOH-treated GST'4-/- mice compared to EtOH-treated wild type controls (p<0.05). Crossing the GST'4-/- mice with the peroxisome proliferator-activated receptor-''null mice (PPAR alpha-/-), which are predisposed to hepatic steatosis, had a significant impact on the degree of EtOH-mediated liver injury in the resulting double knockout (dKO) strain. Serum alanine aminotransferase (ALT) concentrations were significantly higher in the EtOH-treated dKO mice compared to similarly EtOH-treated GSTA4-/- and PPAR alpha-/- mice and wild type controls (p<0.001). EtOH feeding of the dKO mice also resulted in significant elevation of hepatic lipid peroxidation adducts and auto-antibodies directed against these adducts when compared to EtOH-feeding of GST'4-/-, PPAR alpha-/- and wild type control mice (p<0.05). Yet, while markers of oxidative stress and lipid accumulation were significantly elevated in the EtOH-treated dKO mice compared to the GST'4-/- and control mice, we observed no significant differences in these markers when compared to the EtOH-treated PPAR alpha-/- mice, suggesting that the PPAR alpha-/- phenotype is the major driver in these cellular events. However, in the EtOH-treated dKO mice, we did see a more robust inflammatory response as measured by increased mRNA expression of TNF alpha and CD14, a marker for Kuffer cell activation, and increased expression of matrix remodeling markers, alpha SMA, PDGFR, MMP9 when compared to either the GST'4-/- or the PPAR-./- genotype alone (p<0.05). These findings highlight the importance of lipid peroxidation in mediating alcohol-induced liver injury, and provide a model system to study the role of lipid peroxidation products in the progression of alcohol liver disease from steatosis to steatohepatitis and fibrosis.

Last Modified: 10/16/2017
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