The Role of Oxidative Stress in NAFLD-NASH-HCC Transition-Focus on NADPH Oxidases

Abstract

A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.

Keywords: NADPH oxidases; NAFLD; NASH; NOX; hepatocellular carcinoma HCC; oxidative stress.

Figure 1

Molecular oxidative stress-related mechanisms involved in the NAFLD–NASH–HCC transition. Abbreviations: non-alcoholic fatty liver disease, NAFLD; non-alcoholic steatohepatitis, NASH; hepatocellular carcinoma, HCC; malondialdehyde, MDA; 4-hydroxynonenal, 4-HNE; oxidation-specific epitopes, OSEs; receptor for advanced glycation end products, RAGE; reactive oxygen species, ROS; damage-associated molecular patterns, DAMPs.

Figure 2

Schematic representation of subunits forming different NOX active enzymes and their main localization in hepatic cell types. Abbreviations: NADPH oxidase, NOX; hepatic stellate cells, HSCs; Kupffer cells, KCs.

Figure 3

Schematic representation of NOX-induced ROS pathways leading to ECM remodeling during HCC development. NOXs isoforms are differently expressed in hepatic cells involved in NASH–fibrosis–HCC progression. Abbreviations: NADPH oxidase, NOX; hepatic stellate cell, HSC; Kupffer cell, KC; reactive oxygen species, ROS; damage-associated molecular patterns, DAMPs; extracellular matrix, ECM.