Changes in the hepatic mitochondrial and membrane proteome in mice fed a non-alcoholic steatohepatitis inducing diet

Non-alcoholic steatohepatitis (NASH) accounts for a large proportion of cryptic cirrhosis in the Western societies. Nevertheless, we lack a deeper understanding of the underlying pathomolecular processes, particularly those preceding hepatic inflammation and fibrosis. In order to gain novel insights into early NASH-development from the first appearance of proteomic alterations to the onset of hepatic inflammation and fibrosis, we conducted a time-course analysis of proteomic changes in liver mitochondria and membrane-enriched fractions of female C57Bl/6N mice fed either a mere steatosis or NASH inducing diet. This data was complemented by quantitative measurements of hepatic glycerol-containing lipids, cholesterol and intermediates of the methionine cycle. Aside from energy metabolism and stress response proteins, enzymes of the urea cycle and methionine metabolism were found regulated. Alterations in the methionine cycle occur early in disease progression preceding molecular signs of inflammation. Proteins that hold particular promise in the early distinction between benign steatosis and NASH are methyl-transferase Mettl7b, the glycoprotein basigin and the microsomal glutathione-transferase.