Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction

Abstract

AIMTo comprehensively evaluate mitochondrial (dys) function in preclinical models of nonalcoholic steatohepatitis (NASH).METHODSWe 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.RESULTSWhen 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.CONCLUSIONOxidative 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.

Resolution of NASH and hepatic fibrosis by the GLP-1R and GCGR dual-agonist cotadutide via modulating mitochondrial function and lipogenesis

“…Hepatocytes from ob/ob NASH mice displayed significantly reduced basal and maximal oxygen consumption rate (OCR) compared to lean controls ( Fig. 5e , f ), as previously observed 23 , 24 . Ex vivo treatment with Cotadutide or g1437, but not Liraglutide, restored basal and maximal respiratory rates in NASH hepatocytes to similar levels as normal controls ( Fig.…”

Western Diet Causes Obesity-Induced Nonalcoholic Fatty Liver Disease Development by Differentially Compromising the Autophagic Response

“…However, the abolished mt-FAO response in NAFLD can be associated with different mitochondrial alterations, such as reduced oxidative phosphorylation (OXPHOS), diminished ATP production and enhanced sensitivity for mitochondrial permeability transition pore (mPTP) opening [ 12 , 13 , 14 ]. The progression of NAFL towards NASH in a nonreversible manner was reported to involve a prooxidative state and mitochondrial-induced reactive oxygen species (ROS) production, which ultimately alter cellular signaling cascades leading to hepatocellular inflammation and fibrosis [ 15 , 16 , 17 ]. Conversely, recent evidence has questioned the role of oxidative stress as a trigger of NAFL progression.…”

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

“…The present survival analysis data showed that MS-NASH mice better tolerated CCl 4 associated mortality compared to C57Bl/6 mice, which could be attributed to higher catalase activity to oxidative stress, thus, reducing oxidative DNA damage in MS-NASH mice reported by Boland et. al [47].…”