title: Metformin-mediated Bambi expression in hepatic stellate cells induces prosurvival Wnt/β-catenin signaling.
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-β 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/β-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/β-catenin signaling provides a possible mechanistic explanation for this observation. These results suggest that AICAR and metformin may confer disease-specific therapeutic benefits.
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Sydney Medical School, University of Sydney, Westmead, New South Wales, Australia.
authors.forename: Nanthakumar
authors.initials: N
authors.lastname: Subramaniam
authors.forename: Mara H
authors.initials: MH
authors.lastname: Sherman
authors.forename: Renuka
authors.initials: R
authors.lastname: Rao
authors.forename: Caroline
authors.initials: C
authors.lastname: Wilson
authors.forename: Sally
authors.initials: S
authors.lastname: Coulter
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008687:Metformin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000096:biosynthesis*; D051176:beta Catenin / Q000096:biosynthesis*
chemical_list: C485671:BAMBI protein, human; C485673:Bambi protein, rat; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012265:Ribonucleotides; D051153:Wnt Proteins; D051176:beta Catenin; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide