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

Bhaumik Pandya,Ranjitsinh V. Devkar,Ravirajsinh N. Jadeja,Manuela Bartoli,Pamela M. Martin,Menaka C. Thounaojam,Apeksha Joshi,Kapil K. Upadhyay,Hitarthi S. Vyas,Aliasgar Vohra

doi:10.1016/j.redox.2019.101314

Bhaumik Pandya, Ranjitsinh V. Devkar + Show 8 more

Open Access

https://doi.org/10.1016/j.redox.2019.101314

Copy DOI

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.

Highlights

Multitude of metabolic diseases, including non-alcoholic steatohepatitis (NASH), have been implicated to higher consumption of fat-rich and high calorie foods [1]
Carbon monoxide releasing molecule-A1 (CORM-A1) treatment to high fat high fructose (HFHF) fed mice resulted in reduced weight gain and abdominal circumference (P < 0.0001) and showed less fat accumulation as compared to HFHF fed mice
We have investigated the protective effects of the antioxidant gasotransmitter CORM-A1 in a mouse model of NASH

Summary

Introduction

Multitude of metabolic diseases, including non-alcoholic steatohepatitis (NASH), have been implicated to higher consumption of fat-rich and high calorie foods [1]. About 15% of the total obese individuals with symptoms of metabolic syndrome constitute the high-risk group for NASH. Excess lipid accumulation in hepatocytes, high oxidative stress and inflammation are the key players in pathogenesis of NASH [4]. Used symptomatic treatment protocols for NASH include the lipid lowering, anti-diabetic, antioxidants or anti-inflammatory drugs coupled with changes in lifestyle. Patients with NASH develop anomalies in the ultrastructure of mitochondria, impairment of hepatic ATP synthesis and increased mitochondrial ROS production [6,7]. Cytokine production and fatty manifestations in liver causes cell death and overall impairment of liver function [8]

Methods

Results

Conclusion