Acetaldehyde-modified and 4-hydroxynonenal-modified proteins in the livers of rats with alcoholic liver disease

Abstract

modification by acetaldehyde correlates well with the severity Liver proteins form adducts with acetaldehyde and are of liver injury in ethanol-fed rats, whereas modification by modified by products of lipid peroxidation in alcohol-fed anithe lipid peroxidation product 4-HNE shows no correlation mals. It has been hypothesized that the formation of these with the severity of liver injury. (HEPATOLOGY 1997;26:650-modified liver proteins may contribute to liver injury in alco-657.) holic liver disease. The present work was performed to determine the extent of protein modification in rats with experimental alcoholic liver disease. Rats were fed ethanolThe major pathway for ethanol disposition involves alcointragastrically with medium chain triglycerides (MCTs), hol dehydrogenase, an enzyme that catalyzes the conversion palm oil, corn oil, or fish oil. The group fed MCTs and ethanol of ethanol to acetaldehyde. 1 With prolonged alcohol conshowed no liver injury, rats fed palm oil and ethanol showed sumption, the metabolic pathway through cytochrome P450 only fatty liver, rats fed corn oil and ethanol showed fatty 2E1 becomes important. 2 Both alcohol dehydrogenase and liver with moderate necrosis and inflammation, and rats fed cytochrome P450 2E1 generate acetaldehyde from ethanol. 1,2 fish oil and ethanol showed fatty liver with severe necrosisIn recent years, extensive evidence supporting a role for acetand inflammation. Antibodies were raised by using keyhole aldehyde in the detrimental actions of ethanol on the liver limpet hemocyanin modified in vitro by 4-hydroxynonenal (4-has been accumulated. 3 One basis of the toxic effect of acetal-HNE) or acetaldehyde as immunogens. When liver extracts dehyde is the covalent binding of this highly reactive chemiwere examined by Western blot analysis, the intensities of the cal to proteins. 4 Although the adduct formation between acetacetaldehyde-modified protein band (37 kd) in the alcohol-fed aldehyde and hepatic proteins has been well established, 5-11 animals were significantly different among the ethanol-treated its precise role in causing liver injury remains unclear. We groups and correlated with plasma acetaldehyde concentrahave previously detected a protein-acetaldehyde adduct tions. It was strongest in rats fed fish oil and ethanol, followed (PAA) in the livers of rats fed ethanol with both low-and by rats fed palm oil and ethanol and rats fed corn oil and high-fat diets. 5,12 The 37-kd liver protein that forms acetaldeethanol, whereas rats fed MCTs and ethanol showed the hyde adduct in vivo has been identified recently as D 4 -3-weakest intensity. The 37-kd protein-adetaldehyde adduct ketosteroid-5b reductase, 13 a key enzyme involved in bile was located mainly in the pericentral region of the liver. No acid syntheses. acetaldehyde adduct was detected in the control rats that were Another area of investigation in which adduct formation pair-fed with isocaloric amounts of dextrose. Western blot has been proposed to be of pathogenic importance to alcoanalysis using ...

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

“…Autoantibodies against MMA were significantly elevated in sera of chronic alcoholexposed animals [46] and in patients with ALD, and the titers are correlated with the severity of liver damage [11,47,48] and progression of liver fibrosis. Interestingly, adducts accumulate in perivenous regions both in alcohol-fed rats [49,50] and in the liver of alcoholics [51,52] , overlapping with the distribution of fatty accumulation.…”

Ethanol Induces Fatty Acid Synthesis Pathways by Activation of Sterol Regulatory Element-binding Protein (SREBP)

“…Thus, one effect of acetaldehyde could be to reduce the concentration of sterols that influence SCAP activity. One enzyme that metabolizes sterols is known to be inhibited by acetaldehyde, namely ⌬ 4 -3-ketosteroid 5-␤-reductase, an enzyme participating in the bile salt synthetic pathway (37)(38)(39)(40). It is not known if other enzymes that participate in sterol metabolism aside from HMG-CoA reductase are affected by ethanol or acetaldehyde.…”

Global Analysis of Protein Damage by the Lipid Electrophile 4-Hydroxy-2-nonenal

“…However, reactive electrophiles also readily react with proteins. Protein modifications by malondialdehyde, 4-hydroxynonenal (HNE) 1 and 4-oxononenal have been characterized on a limited number of proteins by mass spectrometry (MS) (12)(13)(14)(15)(16)(17)(18)(19)(20) and in tissues by antibody-based methods (21)(22)(23)(24)(25)(26). Although relatively little is known about the target selectivity of oxidant-derived lipid electrophiles in complex proteomes, a broader understanding of this phenomenon would provide a basis for understanding mechanisms of oxidant-induced stress and its role in many disease processes.…”