High fat induced hepatic steatosis and mitochondrial dynamic behaviour: time-dependent adaptation

Mitochondria are dynamic organelles that frequently undergo fission and fusion processes, imbalances in which have recently emerged as important etiological factors in obesity and insulin-resistance. The present works aimed to evaluate the association between mitochondrial dynamic behaviour and hepatic steatosis development when rats were fed with high fat diet for different periods. To this end, hepatic lipid accumulation was monitored in rats fed a control diet (10% J/J, N rats) or a high-fat diet (40% J/J, L rats) for 6 or 24 weeks. Mitochondrial fatty acid oxidation rates and the content of fusion (MFN2, OPA1) and fission (DRP1, Fis1) proteins (by western blot and immunohistochemical analysis) were assessed. After 6 weeks, L rats showed increased hepatic lipid accumulation and beta-oxidation associated with a shift toward mitochondrial fission processes (decreased MFN2 content and increased DRP1 and Fis1 content). This fission phenotype, by enhancing mitochondrial surface area, may improve fatty acids intake and, together with the increase in beta-oxidation, may be useful to avoid excessive fat accumulation. After 24 weeks, the further increase in hepatic lipid accumulation was associated with beta-oxidation impairment and a fission phenotype with a decrease in OPA1 content, too. Bearing in mind the role of OPA1 in stabilizing cristae structure and preventing autophagia, its decrease may be useful to eliminate functional impaired mitochondria and minimize cellular damage.