Published online Apr 28, 2018. doi: 10.3748/wjg.v24.i16.1748
Peer-review started: January 17, 2018
First decision: February 11, 2018
Revised: February 22, 2018
Accepted: February 26, 2018
Article in press: February 25, 2018
Published online: April 28, 2018
To comprehensively evaluate mitochondrial (dys) function in preclinical models of nonalcoholic steatohepatitis (NASH).
We utilized two readily available mouse models of nonalcoholic fatty liver disease (NAFLD) with or without progressive fibrosis: Lepob/Lepob (ob/ob) and FATZO mice on high trans-fat, high fructose and high cholesterol (AMLN) diet. Presence of NASH was assessed using immunohistochemical and pathological techniques, and gene expression profiling. Morphological features of mitochondria were assessed via transmission electron microscopy and immunofluorescence, and function was assessed by measuring oxidative capacity in primary hepatocytes, and respiratory control and proton leak in isolated mitochondria. Oxidative stress was measured by assessing activity and/or expression levels of Nrf1, Sod1, Sod2, catalase and 8-OHdG.
When challenged with AMLN diet for 12 wk, ob/ob and FATZO mice developed steatohepatitis in the presence of obesity and hyperinsulinemia. NASH development was associated with hepatic mitochondrial abnormalities, similar to those previously observed in humans, including mitochondrial accumulation and increased proton leak. AMLN diet also resulted in increased numbers of fragmented mitochondria in both strains of mice. Despite similar mitochondrial phenotypes, we found that ob/ob mice developed more advanced hepatic fibrosis. Activity of superoxide dismutase (SOD) was increased in ob/ob AMLN mice, whereas FATZO mice displayed increased catalase activity, irrespective of diet. Furthermore, 8-OHdG, a marker of oxidative DNA damage, was significantly increased in ob/ob AMLN mice compared to FATZO AMLN mice. Therefore, antioxidant capacity reflected as the ratio of catalase:SOD activity was similar between FATZO and C57BL6J control mice, but significantly perturbed in ob/ob mice.
Oxidative stress, and/or the capacity to compensate for increased oxidative stress, in the setting of mitochondrial dysfunction, is a key factor for development of hepatic injury and fibrosis in these mouse models.
Core tip:ob/ob and FATZO mice developed nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) when fed a high trans-fat, high fructose and high cholesterol diet, in the context of obesity and insulin resistance, but showed differences in liver disease severity including collagen deposition and monocyte/macrophage infiltration. Mitochondrial dysfunction and increased numbers of mitochondria were observed in both models, similar to that reported in human NASH. Oxidative damage and antioxidant capacity were associated with disease severity. FATZO mice displayed increased catalase activity and reduced oxidative DNA damage compared to ob/ob mice, which may explain their lower disease burden.