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Pathogenesis of Alcoholic Liver Disease

  • Gavin E. Arteel
  • David W. CrabbEmail author

Abstract

Alcoholic liver disease (ALD) is a spectrum of injury to the liver that includes steatosis, inflammation, fibrosis, and cirrhosis. Hepatic steatosis is the first manifestation of excessive drinking and, while reversible, signifies the presence of ongoing metabolic stress on the liver which underlies the more serious stages of ALD. Lipid accumulation results from widespread disturbances in the handling of fat by the body (adipose dysfunction), increased de novo synthesis, and impaired fatty acid oxidation and export as VLDL. These metabolic disturbances are driven by oxidative and ER stress, generation of ceramide, abnormal homocysteine metabolism, activation of the innate immune response, and dysfunctional transcriptional control of lipid-metabolizing pathways. The alcoholic fatty liver probably is always mildly inflamed and sensitive to necrosis, apoptosis, and necroptosis when additional stresses are imposed. The most important of these is the exposure to abnormal levels of lipopolysaccharide reaching the liver from an abnormally permeably gut. Inflammation involves particularly innate immune mechanisms, in particular the release of TNFα by the Kupffer cells, and is a prime driver of fibrosis mediated by hepatic stellate cells (HSC). Unconventional contributors to ALD include the complement system, coagulation pathway, and osteopontin. Improved therapies will need to take into consideration the numerous metabolic and signaling pathways deranged in heavy drinkers.

Keywords

Steatosis Inflammation Fibrosis Oxidative stress Cytokines Lipopolysaccharide Innate immunity Apoptosis Necroptosis 

Notes

Acknowledgment

Supported in part by grants P60 AA07611, U01 AA021883, and U01 AA021840 (D.W.C.) and R01 AA021978 (G.E.A.).

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleUSA
  2. 2.Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisUSA
  3. 3.Department of MedicineEskenazi Health SystemIndianapolisUSA

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