Identification of liver proteins altered by type 2 diabetes mellitus in obese subjects

Background Type 2 diabetes mellitus (T2DM) is a well-known factor risk for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in obese patients. Aims To better understand the association between T2DM and NAFLD, global changes in protein expression in diabetic and non-diabetic obese subjects were assessed by a proteomic approach. Methods Liver samples were obtained from diabetic and non-diabetic morbid obese subjects (BMI>40kg/m2). Histological analysis was used to evaluate hepatic steatosis and the degree of anatomopathological alteration. Changes in protein expression were analysed by two-dimentional electrophoresis combined with MALDI-TOF mass spectrometry. Levels of glutathione, carbonyl and 4-HNE protein adducts were used to assess oxidative stress status. Results Of 850 proteins analysed, 33 were differentially expressed in T2DM obese subjects. Of these, 27 were unequivocally identified by mass spectrometry. Analysis of protein sets revealed patterns of decreased abundance in mitochondrial enzymes, proteins involved in methione metabolism, and oxidative stress response. Accordingly, T2DM subjects showed decreased levels of glutathione, the antioxidant byproduct of methionine metabolism via the transsulfuration pathway, and higher levels of protein and lipid oxidative damage. Changes in detoxyfing enzymes, carbohydrate metabolism, proteasome subunits and retinoic acid synthesis were also found. Conclusions The results suggest alterations in mitochondrial function and methionine metabolism as potential contributing factors to increased oxidative stress in liver of obese diabetic patients which may be influencing the development of NAFLD and NASH.