The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) are incompletely understood. We investigated the chronology of whole body, tissue and cellular events that occur during the evolution of diet-induced NASH. Methods: Male C57Bl6 mice were assigned to a fast food (FF, high calorie, high cholesterol, high fructose) or standard chow (SC) diet for 36 weeks (W). Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression and hepatic lipid content were analyzed. Results: Insulin resistance (HOMA IR) increased ten-fold after 4W. Fibrosing NASH was fully established by 16W. Total hepatic lipids increased by 4W and remained 2-3 fold increased throughout. Hepatic triglycerides declined from six-fold increase at 8W to three-fold increase by 36W. In contrast, hepatic cholesterol levels steadily increased from baseline at 8W to two-fold by 36W. Mitochondrial oxygen flux rates of FF mice diet were persistently lower with all the tested substrates (13-276pmoles/CS µmol/min) than SC mice (17-394pmoles/ml/CS µmol/min) and was accompanied by decreased mitochondrial nuclear gene copy number ratios after 4W. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased only at 24W in FF mice. Conclusion: The evolution of NASH is multiphasic, particularly in terms of hepatic lipid composition. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively these observations provide a unique overview of the sequence of changes that co-evolve with the histological evolution of NASH.
- fatty liver
- insulin resistance
- Copyright © 2016, American Journal of Physiology-Gastrointestinal and Liver Physiology