New Potential Biomarker Proteins for Alcoholic Liver Disease Identified by a Comparative Proteomics Approach

Abstract

Chronic alcohol consumption causes hepatic steatosis, which is characterized by a considerable increase in free fatty acid (FFA) and triglyceride levels. To identify the possible proteins involved in the progression to alcoholic hepatosteatosis, we performed proteomic analysis on livers of mice exposed to alcohol. 2D-based proteomic analysis revealed that EtOH exposure in mice changed the expression of 43 proteins compared with that in mice fed a normal diet (ND). The most notable protein changes were proteins involved in Met metabolism and oxidative stress, most of which were significantly downregulated in alcohol-exposed animals. Although non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) seem to share the same molecular processes, the difference between these conditions is still unclear. To address this question, we explored the features of alcoholic hepatosteatosis that were different compared with those of methionine and choline deficient (MCD) diet-induced mice with nonalcoholic liver damage. Although most of the differentially expressed proteins associated with ALD did not significantly differ from those of NAFLD, nine proteins showed considerably different patterns. Of these, ornithine aminotransferase, vitamin D binding protein, and phosphatidylethanolamine-binding protein were considerably upregulated in ALD mice, compared to that in NAFLD and ND mice. However, other proteins including inorganic pyrophosphatase were differentially regulated in MCD mice; however, they did not differ significantly between the alcoholic model and ND control mice. These results suggested that the identified proteins might be useful candidate markers to differentiate ALD from NAFLD. J. Cell. Biochem. 118: 1189-1200, 2017. © 2016 Wiley Periodicals, Inc.

Non-invasive diagnosis and biomarkers in alcohol-related liver disease

“…100,101 Preclinical studies in mouse models of ALD applied proteomic (MALDI-TOF) analysis of livers and identified a cluster of differentially expressed proteins associated with ALD. 102 Interestingly, most of these proteins were also increased in NASH livers and only ornithine aminotransferase, vitamin D binding protein and phosphatidylethanolaminebinding protein were higher in ALD compared to NASH and normal controls. 102 In a mouse model of ALD, proteomic analysis of circulating extracellular vesicles (EVs) revealed a unique cluster or EVassociated proteins that were increased compared to control EVs.…”

“…102 Interestingly, most of these proteins were also increased in NASH livers and only ornithine aminotransferase, vitamin D binding protein and phosphatidylethanolaminebinding protein were higher in ALD compared to NASH and normal controls. 102 In a mouse model of ALD, proteomic analysis of circulating extracellular vesicles (EVs) revealed a unique cluster or EVassociated proteins that were increased compared to control EVs. 103 Among these was heat-shock protein-90 (hsp90) that was also associated with a biological effect in macrophages after exosome transfer both in vitro and in vivo, indicating both the biomarker potential of EV-associated proteins as well as the potential role of EVs in cell-to-cell communication.…”

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

“…Oxidant stress plays a dominant role in the pathogenesis of ALD, as multiple studies have shown that generation of ROS is key for the progression of fatty liver to steatohepatitis and cirrhosis [23,24,25,26,27]. They induce pathological changes such as steatosis, inflammatory cell infiltration, hepatomegaly, fibrosis and cirrhosis [28].…”

Oxidative Stress—A Key Player in the Course of Alcohol-Related Liver Disease

“…The imbalance between de novo lipid synthesis and lipid β-oxidation accompanying alcohol consumption leads to the accumulation of lipid droplets in hepatic parenchyma [ 73 ]. Ethanol metabolism is also associated with up-regulation of sterol regulatory element binding protein 1c (SREBP-1c) and down-regulation of peroxisome proliferator activated receptor alpha (PPARα) [ 74 , 75 ]. Aberrated expression of the abovementioned receptors promotes fatty acid synthesis and simultaneously inhibits β-oxidation [ 76 , 77 ].…”