Liver proteomics in progressive alcoholic steatosis

• Published in: Toxicology and applied pharmacology 2013-02, Vol.266 (3), p.470-480
• Main Authors: Fernando, Harshica, Wiktorowicz, John E., Soman, Kizhake V., Kaphalia, Bhupendra S., Khan, M. Firoze, Shakeel Ansari, G.A.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Addictive behaviors; Adult and adolescent clinical studies; ALCOHOL DEHYDROGENASE; Alcoholic liver disease; Alcoholics; Alcoholism; Alcoholism and acute alcohol poisoning; Aldehyde dehydrogenase; ALDEHYDES; Amino acids; Animals; BETAINE; Betaine-homocysteine S-methyltransferase; Biological and medical sciences; BIOLOGICAL MARKERS; biomarkers; COMPARATIVE EVALUATIONS; DDT; Diets; Disease Models, Animal; ELECTROPHORESIS; Electrophoresis, Gel, Two-Dimensional; ETHANOL; Ethanol - administration & dosage; Ethanol - toxicity; Fatty liver; Fatty Liver, Alcoholic - genetics; Fatty Liver, Alcoholic - metabolism; FEEDING; Gastroenterology. Liver. Pancreas. Abdomen; Gel electrophoresis; GELS; Gene Expression Regulation; HOMOCYSTEINE; Lipid metabolism; LIVER; Liver diseases; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; MASS SPECTROSCOPY; Medical sciences; METABOLISM; METHIONINE; METHYL TRANSFERASES; MULTIVARIATE ANALYSIS; Multivariate regression adaptive splines; Other diseases. Semiology; Protein turnover; Proteomics; Proteomics - methods; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; RATS; Rats, Inbred F344; Regression Analysis; SIMULATION; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Steatohepatitis; Steatosis; TOXICITY; Toxicology; Two dimensional gel electrophoresis
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2012.11.017

Fatty liver is an early stage of alcoholic and nonalcoholic liver disease (ALD and NALD) that progresses to steatohepatitis and other irreversible conditions. In this study, we identified proteins that were differentially expressed in the livers of rats fed 5% ethanol in a Lieber–DeCarli diet daily for 1 and 3months by discovery proteomics (two-dimensional gel electrophoresis and mass spectrometry) and non-parametric modeling (Multivariate Adaptive Regression Splines). Hepatic fatty infiltration was significantly higher in ethanol-fed animals as compared to controls, and more pronounced at 3months of ethanol feeding. Discovery proteomics identified changes in the expression of proteins involved in alcohol, lipid, and amino acid metabolism after ethanol feeding. At 1 and 3months, 12 and 15 different proteins were differentially expressed. Of the identified proteins, down regulation of alcohol dehydrogenase (−1.6) at 1month and up regulation of aldehyde dehydrogenase (2.1) at 3months could be a protective/adaptive mechanism against ethanol toxicity. In addition, betaine-homocysteine S-methyltransferase 2 a protein responsible for methionine metabolism and previously implicated in fatty liver development was significantly up regulated (1.4) at ethanol-induced fatty liver stage (1month) while peroxiredoxin-1 was down regulated (−1.5) at late fatty liver stage (3months). Nonparametric analysis of the protein spots yielded fewer proteins and narrowed the list of possible markers and identified d-dopachrome tautomerase (−1.7, at 3months) as a possible marker for ethanol-induced early steatohepatitis. The observed differential regulation of proteins have potential to serve as biomarker signature for the detection of steatosis and its progression to steatohepatitis once validated in plasma/serum. The figure shows the Hierarchial cluster analysis of differentially expressed protein spots obtained after ethanol feeding for 1 (1–3) and 3 (4–6) months. C and E represent pair-fed control and ethanol-fed rats, respectively. [Display omitted] ► Proteins related to ethanol-induced steatosis and mild steatohepatitis are identified. ► ADH1C and ALDH2 involved in alcohol metabolism are differentially expressed at 1 and 3months. ► Discovery proteomics identified a group of proteins to serve as potential biomarkers. ► Using nonparametric analysis DDT is identified as a possible marker for liver damage.