The Alterations of Mitochondrial Function during NAFLD Progression—An Independent Effect of Mitochondrial ROS Production

Abstract

The progression of non-alcoholic fatty liver (NAFL) into non-alcoholic steatohepatitis implicates multiple mechanisms, chief of which is mitochondrial dysfunction. However, the sequence of events underlying mitochondrial failure are still poorly clarified. In this work, male C57BL/6J mice were fed with a high-fat plus high-sucrose diet for 16, 20, 22, and 24 weeks to induce NAFL. Up to the 20th week, an early mitochondrial remodeling with increased OXPHOS subunits levels and higher mitochondrial respiration occurred. Interestingly, a progressive loss of mitochondrial respiration along “Western diet” feeding was identified, accompanied by higher susceptibility to mitochondrial permeability transition pore opening. Importantly, our findings prove that mitochondrial alterations and subsequent impairment are independent of an excessive mitochondrial reactive oxygen species (ROS) generation, which was found to be progressively diminished along with disease progression. Instead, increased peroxisomal abundance and peroxisomal fatty acid oxidation-related pathway suggest that peroxisomes may contribute to hepatic ROS generation and oxidative damage, which may accelerate hepatic injury and disease progression. We show here for the first time the sequential events of mitochondrial alterations involved in non-alcoholic fatty liver disease (NAFLD) progression and demonstrate that mitochondrial ROS are not one of the first hits that cause NAFLD progression.

Erythritol Improves Nonalcoholic Fatty Liver Disease by Activating Nrf2 Antioxidant Capacity

“…Oxidative stress is a serious pathological process, in which the production of ROS is the main pathological feature. In NAFLD, oxidative stress is the main inducing factor, which is called the second hit, and ROS is the main pathogenic factor of the second hit. , Studies have shown that effective control of ROS production is the main treatment for alleviating NAFLD. , Fortunately, our results confirmed that Ery effectively inhibited the production of ROS in HepG2 cells induced by OA + PA, indicating that Ery has the effect of resisting oxidative stress. This is similar to the study of Shi et al, which found that anthocyanins, the color pigment in natural fruits and vegetables, can resist oxidative damage in cells by blocking ROS production .…”

Bisphenol A Coupled with a High-Fat Diet Promotes Hepatosteatosis through Reactive-Oxygen-Species-Induced CD36 Overexpression

“…These results suggest that BPA and a HFCCD can stimulate the accumulation of lipids in hepatocytes, induce ROS production, and promote the progression of NAFLD. The presence of oxidative stress has been associated with NAFLD/non-alcoholic steatohepatitis (NASH) [ 31 , 32 ]. BPA reportedly promotes the generation of intracellular peroxides and mitochondrial superoxide, the risk of cardiovascular diseases [ 33 ], and the progression of diabetes, obesity, and cancer [ 34 , 35 , 36 ].…”

Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2

“…For example, FA β-oxidation by peroxisomes may increase upon mitochondrial dysfunction, thus exacerbating peroxisomal production of H 2 O 2 . Feeding C57BL/6J mice a western diet has been shown to upregulate ATP-binding cassette sub-family D proteins Abcd1 and Abcd2, the acyl-CoA thioesterases Acot3, Acot4 and Acot8, and acyl-CoA oxidase 1 (Acox1), all of which are involved in peroxisomal FA oxidation [146]. Also, mitochondrial dysfunction during NASH is likely to increase ROS production by CYP2E1 as it is upregulated in livers of affected patients and has a propensity to generate ROS during catalysis [147,148].…”