Signaling mechanisms in alcoholic liver injury: role of transcription factors, kinases and heat shock proteins.
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 NFkappaB, 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.
Mandrekar
Pranoti
P
Liver Center, Department of Medicine, University of Massachusetts Medical School, LRB 213, 364 Plantation Street, Worcester, MA 01605-2324, USA. pranoti.mandrekar@umassmed.edu
D006360:Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000503:physiopathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
D006360:Heat-Shock Proteins; D051193:Toll-Like Receptors; D014157:Transcription Factors; D020929:Mitogen-Activated Protein Kinase Kinases