Emerging role of redox dysregulation in alcoholic and nonalcoholic fatty liver disease

Abstract

Fatty liver disease (FLD), associated with chronic alcohol consumption or obesity, is a serious medical problem. Strong evidence indicates that oxidative stress and dysregulation of redox-sensitive signaling pathways are central to the pathobiology of FLD. Herein, this Forum summarizes current knowledge regarding mechanisms of FLD from both clinical and experimental studies. Special emphasis is given to the role of redox biology disturbances in the initiation and progression of FLD from both chronic alcohol consumption and obesity. Focus areas in this Forum include discussions on the (i) multi-hit hypothesis; (ii) interaction of adipokines and redox signaling pathways; (iii) role of sub-cellular organelle systems (i.e., endoplasmic reticulum and mitochondria); and (iv) contribution of the innate immune system, in FLD. A state-of-the-art discussion is also included highlighting key lessons learned from experimental studies using rodent models of FLD.

FIG. 1.

Current understanding of the pathophysiology of alcoholic steatohepatitis and nonalcoholic steatohepatitis. Recent advances point to the following molecular events being critical for fatty liver disease (FLD) pathology. Insulin resistance from both chronic alcohol consumption and obesity is now recognized as a critical event for development of steatosis: the first-hit of FLD. Early in the disease process the liver adapts to excess free fatty acid (FFA) to prevent triglyceride (TG) accumulation; however, over time these adaptive mechanisms fail resulting to TG accumulation, steatosis, and lipotoxicity. Lipotoxicity can trigger ER stress, lysosomal permeability, and mitochondrial dysfunction. As a consequence, there is increased production of a wide variety of reactive oxygen, nitrogen, and lipid species (RONLS), which dysregulate multiple redox-sensitive signaling pathways leading to increased TG accumulation. The ensuing disruption of mitochondrial function triggers apoptotic and necrotic cell death: key second-hits in FLD pathobiology. In conjunction, release of reactive species from hepatocytes can trigger activation of immune cells and convert the normally quiescent stellate cells to a fibrosis-inducing cell. It is this combination of these events and others presented within this Forum that are involved in the progression from steatosis to steatohepatitis to fibrosis/cirrhosis.