Proteomic Profiling of Liver and Plasma in Chronic Ethanol Feeding Model of Hepatic Alcohol Dehydrogenase-Deficient Deer Mice

Abstract

Background Chronic alcohol abuse, a major risk factor for such diseases as hepatitis and cirrhosis, impairs hepatic alcohol dehydrogenase (ADH, key ethanol metabolizing enzyme). Therefore, differentially altered hepatic and plasma proteomes were identified in chronic ethanol feeding model of hepatic ADH-deficient (ADH−) deer mice to understand the metabolic basis of alcoholic liver disease (ALD). Methods ADH− deer mice were fed 3.5g% ethanol via Lieber-DeCarli liquid diet daily for three months, and histology of the liver assessed. Liver and plasma proteins were separated by 2-dimensional gel electrophoresis. The proteins differentially expressed were identified by MALDI-TOF/TOF mass spectrometry (MS). Results Histology of the liver showed panlobular steatosis and infiltration of T-lymphocytes. Using the criteria of ≥1.5 for fold change (p value ≤0.05) with expectation value (E ≤10−3) and protein score (≥64), eighteen proteins in the livers and five in the plasma of ethanol-fed mice were differentially expressed and identified. Prolyl 4-hydroxylase, cytochrome b-5, endo A cytokeratin, ATP synthase, heat shock 70kD proteins, enoyl CoA hydratase, stress-70 protein, peroxiredoxin 1 and ornithine carbamoyl-transferase were up regulated in the livers. However, carbonic anhydrase 3, mitochondrial ATP synthase, aldolase 2, actin γ, laminin receptor and carbamoyl-phosphate synthase were down regulated. Contrary to the increased expression of creatine kinase m-type, a decreased expression of serine protease inhibitor A3A precursor, sulfated glycoprotein-2 (clusterin) and apolipoprotein E isoforms were found in the plasma of ethanol group. Conclusions Chronic ethanol feeding in ADH− deer mice causes steatosis and infiltration of T-lymphocytes in the livers along with increased expression of proteins involved in ER stress, fibrosis, fatty acid β oxidation and biogenesis, and decreased expression of proteins involved in ATP synthesis, carbohydrate metabolism, in cell regulation and architecture. Reduced expression of various carrier proteins as found in the plasma of ethanol group has a biomarker potential.

Morphological and biochemical effects of weekend alcohol consumption in rats: Role of concentration and gender

“…It has been reported that ethanol favors hepatic steatosis, probably because of the increase of lipogenesis, diminution of lipid transport of the liver, alteration of oxygenation of fatty acids[ 27 ], and even infiltration of monocytes, macrophages, etc ., which are fundamental for pathogenic activity after acute or chronic hepatic injury[ 27 ]. The latter can explain in part the histological findings encountered in our study, where fatty change as well as inflammation comprised the most important changes in weekend alcohol consumption in all of the groups (Table 4 ), probably due to that they are related with the acute damage caused by ethanol to the liver[ 16 - 24 ].…”

Impact of High Fat Diet and Ethanol Consumption on Neurocircuitry Regulating Emotional Processing and Metabolic Function

“…Dr. Charles Lieber and Dr. Leonore DeCarli created a unique model by administering EtOH as part of a nutritionally complete liquid diet (Lieber and DeCarli, 1982 ). This consumption model has been the forerunner in the EtOH research field as a useful tool to study pathological disorders associated with AUD, such as alcoholic liver disease (Dolganiuc et al, 2009 ; Bhopale et al, 2017 ; Guo et al, 2018 ). Another commonly used exposure method is EtOH vapor inhalation which is useful to maintain constant, clinically relevant blood EtOH concentrations and to induce EtOH dependence (Healey et al, 2008 ; Snyder et al, 2019 ).…”

Reversing Epigenetic Alterations Caused by Alcohol: A Promising Therapeutic Direction for Alcoholic Liver Disease

“…The phosphorylation of histone is catalyzed by MAPK, largely in serine 10 and 28 of H3 after alcohol exposure and is generally related to transcriptional activation (Lee and Shukla, ). Acetyl‐CoA generated after alcohol metabolism can participate in the tricarboxylic acid cycle, which provides ATP or GTP, whose phosphate can further be transferred to N‐terminal amino acid residues under the mediation of MAPK (Bhopale et al., ). Different alcoholic drinking patterns have diverse effects on the epigenetic modification of histone.…”