Carbon monoxide releasing molecule-A1 improves nonalcoholic steatohepatitis via Nrf2 activation mediated improvement in oxidative stress and mitochondrial function

Abstract

Nuclear factor-erythroid 2 related factor 2 (Nrf2)-mediated signaling plays a central role in maintaining cellular redox homeostasis of hepatic cells. Carbon monoxide releasing molecule-A1 (CORM-A1) has been reported to stimulate up-regulation and nuclear translocation of Nrf2 in hepatocytes. However, the role of CORM-A1 in improving lipid metabolism, antioxidant signaling and mitochondrial functions in nonalcoholic steatohepatitis (NASH) is unknown. In this study, we report that CORM-A1 prevents hepatic steatosis in high fat high fructose (HFHF) diet fed C57BL/6J mice, used as model of NASH. The beneficial effects of CORM-A1 in HFHF fed mice was associated with improved lipid homeostasis, Nrf2 activation, upregulation of antioxidant responsive (ARE) genes and increased ATP production. As, mitochondria are intracellular source of reactive oxygen species (ROS) and important sites of lipid metabolism, we further investigated the mechanisms of action of CORM-A1-mediated improvement in mitochondrial function in palmitic acid (PA) treated HepG2 cells. Cellular oxidative stress and cell viability were found to be improved in PA + CORM-A1 treated cells via Nrf2 translocation and activation of cytoprotective genes. Furthermore, in PA treated cells, CORM-A1 improved mitochondrial oxidative stress, membrane potential and rescued mitochondrial biogenesis thru upregulation of Drp1, TFAM, PGC-1α and NRF-1 genes. CORM-A1 treatment improved cellular status by lowering glycolytic respiration and maximizing OCR. Improvement in mitochondrial respiration and increment in ATP production in PA + CORM-A1 treated cells further corroborate our findings. In summary, our data demonstrate for the first time that CORM-A1 ameliorates tissue damage in steatotic liver via Nrf2 activation and improved mitochondrial function, thus, suggesting the anti-NASH potential of CORM-A1.

Carbon Monoxide Being Hydrogen Sulfide and Nitric Oxide Molecular Sibling, as Endogenous and Exogenous Modulator of Oxidative Stress and Antioxidative Mechanisms in the Digestive System

“…Moreover, CORM-A1 significantly ameliorated mitochondrial function in palmitic acid-(PA-) treated HepG2 cells via Nrf2 translocation and activation of cytoprotective gene expression. Furthermore, in PA-treated cells, CORM-A1 improved mitochondrial oxidative stress, mitochondrial membrane potential, and rescued mitochondrial biogenesis [92].…”

“…Interestingly, mice that received a lethal dose of 7 Oxidative Medicine and Cellular Longevity APAP died but those cotreated with CORM-A1 showed a 50% survival [79]. Additionally, CORM-A1 prevented hepatic steatosis in high-fat high-fructose (HFHF) diet fed mice, used as a model of nonalcoholic steatohepatitis (NASH) [92]. The beneficial effects of CORM-A1 in HFHF fed mice were associated with improved lipid homeostasis, Nrf2 activation, upregulation of antioxidant-responsive (ARE) genes, and increased ATP production [92].…”

“…Additionally, CORM-A1 prevented hepatic steatosis in high-fat high-fructose (HFHF) diet fed mice, used as a model of nonalcoholic steatohepatitis (NASH) [92]. The beneficial effects of CORM-A1 in HFHF fed mice were associated with improved lipid homeostasis, Nrf2 activation, upregulation of antioxidant-responsive (ARE) genes, and increased ATP production [92]. The effects of HO-1 and its enzymatic activity products CO, BV, and iron/ferritin were also assessed in a mouse model of inflammatory liver damage induced by bacterial wall cytotoxin lipopolysaccharide (LPS) and hepatocytespecific transcription inhibitor D-galactosamine (GalN).…”

“…Recently, the possible contribution of mitochondria as the molecular targets of CO has been suggested [92,96,98]. These key organelles for cell energy supply play a crucial role in the initiation and progression of many diseases following oxidative stress-induced damage [98].…”

Capsaicin Alleviates the Deteriorative Mitochondrial Function by Upregulating 14-3-3η in Anoxic or Anoxic/Reoxygenated Cardiomyocytes

“…Previous studies documented that decreased complex I/III activities result in excessive ROS accumulation and influence energy metabolism [18][19][20][21]. A metabolic disorder is closely associated with the mitochondrial dysfunction of cardiomyocytes during A/R injury [22,23]. During anoxia, insufficient oxygen supply decreases in oxygen consumption rates (OCR) and adenosine triphosphate (ATP) production inhibiting the ability to meet the demands of energy metabolism and ultimately inducing an irreversible injury on cardiomyocytes [24].…”