| First Author | Ronis MJ | Year | 2015 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 308 |
| Issue | 5 | Pages | G403-15 |
| PubMed ID | 25501545 | Mgi Jnum | J:223850 |
| Mgi Id | MGI:5660474 | Doi | 10.1152/ajpgi.00154.2014 |
| Citation | Ronis MJ, et al. (2015) Increased 4-hydroxynonenal protein adducts in male GSTA4-4/PPAR-alpha double knockout mice enhance injury during early stages of alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 308(5):G403-15 |
| abstractText | To test the significance of lipid peroxidation in the development of alcoholic liver injury, an ethanol (EtOH) liquid diet was fed to male 129/SvJ mice (wild-type, WT) and glutathione S-transferase A4-4-null (GSTA4-/-) mice for 40 days. GSTA4-/- mice were crossed with peroxisome proliferator-activated receptor-alpha-null mice (PPAR-alpha-/-), and the effects of EtOH in the resulting double knockout (dKO) mice were compared with the other strains. EtOH increased lipid peroxidation in all except WT mice (P < 0.05). Increased steatosis and mRNA expression of the inflammatory markers CXCL2, tumor necrosis factor-alpha (TNF-alpha), and alpha-smooth muscle actin (alpha-SMA) were observed in EtOH GSTA4-/- compared with EtOH WT mice (P < 0.05). EtOH PPAR-alpha-/- mice had increased steatosis, serum alanine aminotransferase (ALT), and hepatic CD3+ T cell populations and elevated mRNA encoding CD14, CXCL2, TNF-alpha, IL-6, CD138, transforming growth factor-beta, platelet-derived growth factor receptor-beta (PDGFR-beta), matrix metalloproteinase (MMP)-9, MMP-13, alpha-SMA, and collagen type 1 compared with EtOH WT mice. EtOH-fed dKO mice displayed elevation of periportal hepatic 4-hydroxynonenal adducts and serum antibodies against malondialdehyde adducts compared with EtOH feeding of GSTA4-/-, PPAR-alpha-/-, and WT mice (P < 0.05). ALT was higher in EtOH dKO mice compared with all other groups (P < 0.001). EtOH-fed dKO mice displayed elevated mRNAs for TNF-alpha and CD14, histological evidence of fibrosis, and increased PDGFR, MMP-9, and MMP-13 mRNAs compared with the EtOH GSTA4-/- or EtOH PPAR-alpha-/- genotype (P < 0.05). These findings demonstrate the central role lipid peroxidation plays in mediating progression of alcohol-induced necroinflammatory liver injury, stellate cell activation, matrix remodeling, and fibrosis. |
