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. 2015 Mar 1;308(5):G403-15.
doi: 10.1152/ajpgi.00154.2014. Epub 2014 Dec 11.

Increased 4-hydroxynonenal protein adducts in male GSTA4-4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease

Martin J J Ronis  1 , Kelly E Mercer  2 , Brenda Gannon  3 , Bridgette Engi  4 , Piotr Zimniak  5 , Colin T Shearn  6 , David J Orlicky  6 , Emanuele Albano  7 , Thomas M Badger  2 , Dennis R Petersen  6
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Increased 4-hydroxynonenal protein adducts in male GSTA4-4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease (V体育平台登录)

Martin J J Ronis et al. Am J Physiol Gastrointest Liver Physiol. .

Abstract (V体育安卓版)

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 VSports手机版. 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. .

Keywords: 4-hydroxynonenal; alcohol; glutathione S-transferase A4–4; lipid peroxidation; liver; peroxisome proliferator-activated receptor-α. V体育安卓版.

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Fig. 1.
Fig. 1.
Representative hematoxylin and eosin-stained liver sections from wild-type (WT), glutathione S-transferase A4–4-null (GSTA4−/−), peroxisome proliferator-activated receptor-α-null mice (PPAR-α−/−), and double knockout (dKO mice) fed a Lieber-DeCarli ethanol (EtOH) or control pair-fed (PF) diet as described in materials and methods. Magnification, ×10. SV, 129/SvJ mice. CV, central vein; PT, portal triad.
Fig. 2.
Fig. 2.
Immunohistochemical characterization of hydroxynonenal (4-HNE) adducts and overall lipid peroxidation in PF and EtOH-fed WT, GSTA4−/−, PPAR-α−/−, and dKO mice. A: representative sections of 4-HNE staining intensity between the groups. B: quantification of 4-HNE adducts expressed as a ratio of zone 1 to zone 3. C: thiobarbituric acid reactive substrate (TBARS). Data expressed as means ± SE. Groups with different letter subscripts are significant from each other, P < 0.05.
Fig. 3.
Fig. 3.
Accumulation of autoantibodies to malondialdehyde (MDA) and 4-HNE protein adducts in the serum of WT, GSTA4−/−, PPAR-α−/−, and dKO mice receiving EtOH. A: MDA. B: 4-HNE. Data expressed as means ± SE. Groups with different letter subscripts are significant from each other, P < 0.05.
Fig. 4.
Fig. 4.
Effects of EtOH on hepatic Kupffer cell activation and leukocyte infiltration and activation in WT, GSTA4−/−, PPAR-α−/−, and dKO mice. A: CD14 mRNA expression. B: CD68:CD45 ratio. Data expressed as means ± SE. Groups with different letter subscripts are significant from each other, P < 0.05.
Fig. 5.
Fig. 5.
Effects of high-fat PF and EtOH on molecular markers of T-helper cells (CD4 mRNA), hepatic Th-1 response (IFN-γ mRNA), B cell recruitment (B220 mRNA), and B cell differentiation to plasma cells (CD138 mRNA) in WT, GSTA4−/−, PPAR-α−/−, and dKO mice. Data expressed as means ± SE. Groups with different letter subscripts are significant from each other, P < 0.05.
Fig. 6.
Fig. 6.
Effects of EtOH on hepatic macrophage and CD3+ T cell populations in PPAR-α−/− and dKO mice. Top: representative immunohistochemical staining of liver sections from pair-fed (PF) and EtOH-treated mice. Left: macrophage staining with F4/80. Right: T cell staining with CD3. Bottom: quantitation of immunohistochemical staining in 4 random liver sections from each treatment group. Data expressed as means ± SE. EtOH groups with * are significant from PF, P < 0.05.
Fig. 7.
Fig. 7.
The appearance of fibrosis in EtOH-treated WT, GSTA4−/−, PPAR-α−/−, and dKO mice. Picrosirius red staining of collagen fibers. Magnification ×10.
Fig. 8.
Fig. 8.
Changes in hepatic markers of stellate cell activation, matrix remodeling, and fibrosis in WT, GSTA4−/−, PPAR-α−/−, and dKO mice receiving EtOH and PF diets. Gene expression was measured by real-time RT PCR. A: collagen type 1. B: α-smooth muscle actin (α-SMA). C: platelet-derived growth factor-β receptor (PDGFR). D: matrix metalloproteinase 9 (MMP-9). E: MMP-13. Data expressed as means ± SE. Groups with different letter subscripts are significant from each other, P < 0.05.
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VSports app下载 - References

    1. Abdelmegeed MA, Yoo SH, Henderson LE, Gonzalez FJ, Woodcroft KJ, Song BJ. PPAR alpha expression protects male mice from high fat-induced nonalcoholic fatty liver. J Nutr 141: 603–610, 2011. - V体育平台登录 - PMC - PubMed
    1. Albano E. Oxidative mechanisms in the pathogenesis of alcoholic liver disease. Mol Aspects Med 29: 9–16, 2008. - PubMed
    1. Arteel GE. Oxidants and antioxidants in alcohol-induced liver disease. Gastroenterology 124: 779–790, 2003. - PubMed
    1. Balogh LM, Atkins WM. Interactions of glutathione transferases with 4-hydroxynonenal. Drug Metab Rev 43: 165–178, 2011. - V体育平台登录 - PMC - PubMed
    1. Basaranoglu M, Basaranoglu G, Senturk H. From fatty liver to fibrosis: a tale of “second hit”. World J Gastroenterol 19: 1158–1165, 20013. - PMC - PubMed

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