Oxidative stress and redox signaling mechanisms of alcoholic liver disease: updated experimental and clinical evidence

Abstract

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the United States and Europe. The spectrum of ALD ranges from fatty liver to alcoholic hepatitis and cirrhosis, which may eventually lead to hepatocellular carcinoma. In developed countries as well as developing nations, ALD is a major cause of end-stage liver disease that requires liver transplantation. The most effective therapy for ALD is alcohol abstinence; however, for individuals with severe ALD and those in whom alcohol abstinence is not achievable, targeted therapies are absolutely necessary. In this context, advances of our understanding of the pathophysiology of ALD over the past two decades have contributed to the development of therapeutic modalities (e.g., pentoxifylline and corticosteroids) for the disease although the efficacy of the available treatments remains limited. This article is intended to succinctly review the recent experimental and clinical findings of the involvement of oxidative stress and redox signaling in the pathophysiology of ALD and the development of mechanistically based antioxidant modalities targeting oxidative stress and redox signaling mechanisms. The biochemical and cellular sources of reactive oxygen and nitrogen species (ROS/RNS) and dysregulated redox signaling pathways associated with alcohol consumption are particularly discussed to provide insight into the molecular basis of hepatic cell dysfunction and destruction as well as tissue remodeling underlying ALD.

Fig. 1

Spectrum of alcoholic liver disease (ALD). It is of note that although cirrhosis is usually the primary pathophysiological process that leads to the development of hepatocellular carcinoma, ALD may progress into liver cancer without necessarily going through cirrhosis.

Fig. 2

Sequential metabolism of ethanol to form acetaldehyde and acetate. As illustrated, the metabolism of ethanol occurs in the liver (also in many other types of tissues) via three enzymatic systems, ADH, P4502E1, and catalase, which are primarily located in cytosol, endoplasmic reticulum membrane (microsomes), and peroxisomes, respectively. ALDH is located in mitochondria and cytosol. ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase.

Fig. 3

Involvement of Nrf2 signaling in the pathophysiology of alcoholic liver disease (ALD). Activation of Nrf2 signaling and Nrf2-dependent antioxidants and anti-inflammatory enzymes may act as a compensatory protective mechanism in ALD. Consequently, comprised Nrf2 functionality may aggravate the pathophysiology of ALD. See text for more detailed description. ROS, reactive oxygen species; LPS, lipopolysaccharide.

Fig. 4

Schematic illustration of the overall involvement of oxidative/electrophilic stress and dysregulated inflammation in the pathophysiology of alcoholic fatty liver disease. See text for more detailed description. LPS, lipopolysaccharide; ROS, reactive oxygen species.