title: Increased 4-hydroxynonenal protein adducts in male GSTA4-4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease.
abstract: 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-α-null mice (PPAR-α-/-), 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-α (TNF-α), and α-smooth muscle actin (α-SMA) were observed in EtOH GSTA4-/- compared with EtOH WT mice (P < 0.05). EtOH PPAR-α-/- mice had increased steatosis, serum alanine aminotransferase (ALT), and hepatic CD3+ T cell populations and elevated mRNA encoding CD14, CXCL2, TNF-α, IL-6, CD138, transforming growth factor-β, platelet-derived growth factor receptor-β (PDGFR-β), matrix metalloproteinase (MMP)-9, MMP-13, α-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-α-/-, 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-α and CD14, histological evidence of fibrosis, and increased PDGFR, MMP-9, and MMP-13 mRNAs compared with the EtOH GSTA4-/- or EtOH PPAR-α-/- 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.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas; MartinJRonis@msn.com.
authors.forename: Martin J J
authors.initials: MJ
authors.lastname: Ronis
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas;
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Mercer
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
authors.forename: Brenda
authors.initials: B
authors.lastname: Gannon
authors.affiliation: Department of Laboratory Animal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
authors.forename: Bridgette
authors.initials: B
authors.lastname: Engi
authors.affiliation: Arkansas Children's Nutrition Center, Little Rock, Arkansas;
authors.forename: Piotr
authors.initials: P
authors.lastname: Zimniak
authors.affiliation: University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Colin T
authors.initials: CT
authors.lastname: Shearn
authors.affiliation: University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.affiliation: Department of Medical Sciences, University A Avogadro of East Piedmonte, Novara, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Albano
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas;
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Badger
authors.affiliation: University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Petersen
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000447:Aldehydes / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000097:blood; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D015227:Lipid Peroxidation; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000276:immunology / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D000447:Aldehydes; D000906:Antibodies; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D047493:PPAR alpha; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C544013:alpha-smooth muscle actin, mouse; C529117:GSTA4-4 protein, mouse; D005982:Glutathione Transferase; D000410:Alanine Transaminase; D020797:Receptor, Platelet-Derived Growth Factor beta; D020782:Matrix Metalloproteinases; C027576:4-hydroxy-2-nonenal
keywords: 4-hydroxynonenal; alcohol; glutathione S-transferase A4–4; lipid peroxidation; liver; peroxisome proliferator-activated receptor-α