Focus on: Alcohol and the liver

Abstract

Thirty-five years ago Charles Lieber and colleagues (1975) published a seminal article in liver research, showing that alcohol itself is the primary cause for the higher prevalence of liver disease seen in alcoholic patients and not dietary deficiencies and malnutrition that often accompany alcoholism. Their groundbreaking research dispelled previously held theories that alcohol was not a major cause of liver damage and led to several decades of study of the deleterious effects of alcohol and its metabolism on the liver. Since that early study, clinical and experimental studies have continued to show a firm connection between high amounts of alcohol consumption and liver disease. This article tracks advances in alcohol-related liver disease research over the past 40 years and describes how these discoveries are helping scientists to gain insight into therapeutic targets that may help to combat this life-threatening disease.

Figure 1

Progression of alcoholic liver disease in heavy drinkers.

Figure 2

Proposed mechanism for alcoholic liver disease. Chronic alcohol abuse increases gut permeability resulting in high circulating endotoxin that reaches the liver via portal circulation. Endotoxin (lipopolysaccharide or LPS) is recognized by the Toll-like receptor (TLR)-4 complex on resident macrophages or Kupffer cells in the liver, leading to production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, and resulting in injury to liver cells (hepatocytes).

Figure 3

The Toll-like receptor (TLR)-4 signaling pathway in alcoholic liver disease. Engagement of the TLR-4 receptor results in activation of two distinct pathways: The myeloid differentiation primary response gene 88 (MyD88)-dependent pathway, which results in activation of nuclear factor (NF) κB and proinflammatory cytokines and the MyD88-independent pathway, which activates transcription factor interferon regulatory factor (IRF) 3 and induces type I interferons. NOTE: I κkα, I κB kinase α; Iκkβ, IκB kinase β; p65, subunit 65 kD; p50, subunit 50 kD; Ikβ, Iκβ kinase; Ikkγ, IκB kinase γ; IRAK1/4, interleukin 1/4 receptor–associated kinase; TRAF6, TNF receptor–associated factor 6; TRAF3, TNF receptor–associated factor 3; TBK, TANK-binding kinase; TRIF, TIR domain–containing adaptor–inducing IFNβ; TRAP, Toll-interleukin 1 receptor (TIR) domain–containing adaptor protein; TRAM, TRIF-related adaptor molecule; TBK/IKKɛ, TANK binding kinase.