Editorial
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World J Hepatol. Aug 27, 2010; 2(8): 295-301
Published online Aug 27, 2010. doi: 10.4254/wjh.v2.i8.295
Mallory-Denk body pathogenesis revisited
Samuel W French, Fawzia Bardag-Gorce, Jun Li, Barbara A French, Joan Oliva
Samuel W French, Joan Oliva, Barbara A French, Jun Li, Fawzia Bardag-Gorce, Department of Pathology, Harbor-UCLA Medical Center, CA 90509, United States
Author contributions: Oliva J, French BA, Li J and Bardag-Gorce F equally contributed to this work, and French SW wrote the manuscript.
Supported by the NIH/NIAAA 8116 and by Alcohol Center Grant on Liver and Pancreas P50-011999, Morphology Core
Correspondence to: Samuel W French, Professor, Department of Pathology, Harbor-UCLA Medical Center, 1000 W. Carson St., Torrance, CA 90509, United States. sfrench@labiomed.org
Telephone: +1-310-2222643 Fax: +1-310-2225333
Received: May 4, 2010
Revised: July 7, 2010
Accepted: July 14, 2010
Published online: August 27, 2010
Abstract

This editorial reviews the recent evidence showing that Mallory-Denk bodies (MDBs) form in hepatocytes as the result of a drug-induced shift from the 26s proteasome formation to the immunoproteasome formation. The shift is the result of changes in gene expression induced in promoter activation, which is induced by the IFNγ and TNFα signaling pathway. This activates TLR 2 and 4 receptors. The TLR signaling pathway stimulates both the induction of a cytokine proinflammatory response and an up regulation of growth factors. The MDB- forming hepatocytes proliferate as a result of the increase in growth factor expression by the MDB- forming cells, which selectively proliferate in response to drug toxicity. All of these mechanisms are induced by drug toxicity, and are prevented by feeding the methyl donors SAMe and betaine, supporting the epigenetic response of MDB formation.

Keywords: Toll-like receptor; Proinflammatory; Methyl donors; Epigenetic processes; Drug toxicity; 26s Proteasome; Immunoproteasome