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World J Gastroenterol. Oct 7, 2007; 13(37): 4979-4985
Published online Oct 7, 2007. doi: 10.3748/wjg.v13.i37.4979
Signaling mechanisms in alcoholic liver injury: Role of transcription factors, kinases and heat shock proteins
Pranoti Mandrekar
Pranoti Mandrekar, Liver Center, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605-2324, United States
Author contributions: All authors contributed equally to the work.
Supported by NIAAA grant AA14238
Correspondence to: Pranoti Mandrekar, PhD, Assistant Professor of Medicine, Liver Center, Department of Medicine, University of Massachusetts Medical School, LRB 213, 364 Plantation Street, Worcester, MA 01605-2324, United States. pranoti.mandrekar@umassmed.edu
Telephone: +1-508-8565391 Fax: +1-508-8564770
Received: June 30, 2007
Revised: July 23, 2007
Accepted: July 26, 2007
Published online: October 7, 2007
Abstract

Alcoholic liver injury comprises of interactions of various intracellular signaling events in the liver. Innate immune responses in the resident Kupffer cells of the liver, oxidative stress-induced activation of hepatocytes, fibrotic events in liver stellate cells and activation of liver sinusoidal endothelial cells all contribute to alcoholic liver injury. The signaling mechanisms associated with alcoholic liver injury vary based on the cell type involved and the extent of alcohol consumption. In this review we will elucidate the oxidative stress and signaling pathways affected by alcohol in hepatocytes and Kupffer cells in the liver by alcohol. The toll-like receptors and their down-stream signaling events that play an important role in alcohol-induced inflammation will be discussed. Alcohol-induced alterations of various intracellular transcription factors such as NFκB, PPARs and AP-1, as well as MAPK kinases in hepatocytes and macrophages leading to induction of target genes that contribute to liver injury will be reviewed. Finally, we will discuss the significance of heat shock proteins as chaperones and their functional regulation in the liver that could provide new mechanistic insights into the contributions of stress-induced signaling mechanisms in alcoholic liver injury.

Keywords: TNFα, Toll-like receptors, NFκB, Heat shock proteins, Mitogen-activated protein kinases