Mechanisms and cell signaling in alcoholic liver disease

Abstract

Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60%. The poor prognosis of ALD implies that preventing disease progression would be more effective than treating end-stage liver disease. An obvious avenue of prevention would be to remove the damaging agent; however, the infamously high rate of recidivism in alcoholics makes maintaining abstinence a difficult treatment goal to prevent ALD. Indeed, although the progression of ALD is well-characterized, there is no universally accepted therapy available to halt or reverse this process in humans. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of ALD, rational targeted therapy can be developed to treat or prevent ALD. The purpose of this review is to summarize the established and proposed mechanisms by which chronic alcohol abuse damages the liver and to highlight key signaling events known or hypothesized to mediate these effects.

Figure 1. Proposed mechanism by which alcohol causes alcoholic liver disease

Alcoholic liver disease is a chronic disease of the liver that encompasses fatty liver (steatosis) inflammation (hepatitis) and fibrosis/cirrhosis. Effects of alcohol exposure that are proposed to initiate and mediate the progression of the disease include alcohol metabolism, oxidative stress and priming and sensitization of the inflammatory response.

Figure 2. Oxidative metabolism of alcohol by the liver

Alcohol (CH₃CH₂OH) is oxidized to acetaldehyde (CH₃CHO) by three enzyme systems: the microsomal ethanol oxidizing system (MEOS), alcohol dehydrogenase (ADH) and catalase (CAT). Acetaldehyde, in turn, is metabolized to acetate (CH³COO⁻) by aldehyde dehydrogenase (ALDH) in the mitochondria. The metabolic and biochemical effects of alcohol metabolism might contribute to ADH.

Figure 3. Enhancement of cell signaling caused by alcohol

In LPS-exposed macrophages, toll-like receptor TLR4 is activated, resulting in MyD88-dependent or MyD88-independent activation of MAP kinases and their downstream signaling molecules such as AP-1, EGR-1, NF-κB and HuR. These are inducers of TNFα transcription and all pathways are enhanced by alcohol exposure. Alcohol also downregulates cAMP via inducing PDE4B. This decrease in cAMP results in a disinhibition of NF-κB, which further enhances TNFα transcription.

Figure 4. Effect of alcohol on the transmethylation pathway

The transmethylation pathway is the critical supplier of methyl groups to the cell. Under normal conditions, most of the S-adenosylmethionine (SAM) generated is used in transmethylation reactions, in which SAM is converted to S-adenosyl homocysteine (SAH) by transferring the methyl group to diverse biological acceptors. SAH is then converted to homocysteine (HC) and adenosine in a reversible reaction catalyzed by SAH hydrolase. The conversion of homocysteine to methionine is an essential reaction to conserve methionine (MET), detoxify homocysteine and produce SAM. Ethanol directly or indirectly impairs the formation of SAM from MET by methionine adenosyl transferases (MAT). Alcohol also impairs the remethylation of HC to MET by both folate-dependent methionine synthase (MS) and by betaine homocysteine methyltransferase (BHMT).

Figure 5. Fibrin metabolism

Cross-linked fibrin deposition is initiated by activation of the coagulation cascade through thrombin. PAI-1 inhibits the activity of the plasminogen activators uPA and tPA, blocking the activation of plasmin, thereby blunting fibrinolysis of fibrin matrices to fibrin degradation products (FDP).