NDLI: Metformin-mediated Bambi expression in hepatic stellate cells induces prosurvival Wnt/ß-catenin signaling.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Subramaniam, Nanthakumar Sherman, Mara H. Rao, Renuka Wilson, Caroline Coulter, Sally Atkins, Annette R. Evans, Ronald M. Liddle, Christopher Downes, Michael
Description	Country affiliation: Australia Author Affiliation: Subramaniam N ( Storr Liver Unit, Westmead Millennium Institute and Sydney Medical School, University of Sydney, Westmead, New South Wales, Australia.)
Abstract	AMP-activated protein kinase (AMPK) regulates lipid, cholesterol, and glucose metabolism in specialized metabolic tissues, such as muscle, liver, and adipose tissue. Agents that activate AMPK, such as metformin and 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), have beneficial effects on liver glucose and lipid metabolism. In addition, AMPK activation in proliferating hepatic stellate cells (HSC) induces growth arrest and inhibits hepatic fibrosis. As metformin and AICAR act in different ways to achieve their effects, our aim was to examine the effects of AMPK activation in quiescent HSCs with these two agents on HSC function. We found that phospho-AMPK levels were markedly upregulated by both AICAR and metformin in quiescent HSCs. However, although AICAR treatment induced cell death, cells treated with metformin did not differ from untreated controls. AICAR-mediated HSC cell death was paralleled by loss of expression of the TGF-ß decoy receptor Bambi, whereas metformin increased Bambi expression. Transfection of siRNA-Bambi into HSCs also induced cell death, mimicking the effects of AICAR, whereas overexpression of Bambi partially rescued AICAR-treated cells. As Bambi has previously been shown to promote cell survival through Wnt/ß-catenin signaling, a reporter incorporating binding sites for a downstream target of this pathway was transfected into HSCs and was induced. We conclude that although AICAR and metformin both activate AMPK in quiescent HSCs, AICAR rapidly induced cell death, whereas metformin-treated cells remained viable. The finding that metformin increases Bambi expression and activates Wnt/ß-catenin signaling provides a possible mechanistic explanation for this observation. These results suggest that AICAR and metformin may confer disease-specific therapeutic benefits.
File Format	HTM / HTML
ISSN	19406207
e-ISSN	19406215
DOI	10.1158/1940-6207.CAPR-12-0053
Journal	Cancer Prevention Research
Issue Number	4
Volume Number	5
Language	English
Publisher	American Association for Cancer Research
Publisher Date	2012-04-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Oncology Hepatic Stellate Cells Metabolism Hypoglycemic Agents Pharmacology Membrane Proteins Biosynthesis Metformin Wnt Proteins Beta Catenin Amp-activated Protein Kinases Aminoimidazole Carboxamide Analogs & Derivatives Animals Apoptosis Inflammation Lipopolysaccharides Rats, Sprague-dawley Ribonucleotides Signal Transduction Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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Metformin-mediated Bambi expression in Hepatic Stellate Cells induces pro-survival Wnt/β-catenin signaling

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