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Gastroenterology. 2012 Jan;142(1):130-139.e4. doi: 10.1053/j.gastro.2011.09.033. Epub 2011 Sep 21.

Liver fibrosis protects mice from acute hepatocellular injury.

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1
Laboratoire d'Hépatologie Cellulaire du Centre de Recherche du CHUM-Hôpital Saint-Luc, Montréal, Québec, Canada.

Abstract

BACKGROUND & AIMS:

Development of fibrosis is part of the pathophysiologic process of chronic liver disease. Although it is considered deleterious, it also represents a form of tissue repair. Deposition of extracellular matrix changes the cellular environment of the liver; we investigated whether it increases resistance to noxious stimuli and the role of changes in intracellular signaling to hepatocytes in mediating this effect.

METHODS:

Primary cultures of mouse hepatocytes were exposed to type I collagen (COL1); cell injury was assessed by morphologic and biochemical criteria. The expression of Bcl-2 family members was evaluated by immunoblot analyses. Activation of extracellular signal-regulated kinase (ERK) was assessed using phospho-specific antibodies. Liver fibrosis was induced by repeated administration of thioacetamide or carbon tetrachloride to mice; mice were then exposed to Fas antibodies.

RESULTS:

Hepatocytes exposed to COL1 were more resistant to a variety of hepatotoxins, in a dose-dependent manner, and had lower levels of Bad, Bid, and Bax proapoptotic proteins compared with control hepatocytes. Activation of ERK1/2 was stronger and quicker in hepatocytes exposed to COL1. The MEK1/2 inhibitors U0126 and PD98059 reversed the protective effects of COL1 and the decrease in proapoptotic proteins. Hepatocytes isolated from ERK1(-/-) mice were insensitive to the protective effect of COL1. Fibrotic livers from wild-type mice had high levels of phospho-ERK1 and were resistant to Fas-induced cell death. ERK1(-/-) mice lost this effect.

CONCLUSIONS:

Production of COL1 during liver fibrosis induces a hepatoprotective response that is mediated by activation of ERK1 signaling.

PMID:
21945831
DOI:
10.1053/j.gastro.2011.09.033
[Indexed for MEDLINE]

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