Metformin regulates palmitate-induced apoptosis and ER stress response in HepG2 liver cells.
The excessive supply of fatty acids to the liver contributes to hepatic insulin resistance and endoplasmic reticulum (ER) stress associated with obesity or type 2 diabetes mellitus. Furthermore, excess and/or prolonged ER stress contributes to hepatic cell death deteriorating nonalcoholic fatty liver disease to steatohepatitis. The aim of this study was to investigate the effects of metformin on palmitate-induced ER stress and hepatic insulin resistance in HepG2 cells. Metformin significantly inhibited palmitate-induced cell death and apoptosis via caspase-3 activation. Metformin also blocked the induction of ER stress proteins (GRP78, Chop, Cleaved ATF-6, p-eIF2 alpha and XBP-1) and regulated serine phosphorylation of IRS-1. Metformin may therefore protect hepatocytes from death induced by saturated fatty acids. These data may also provide a further rationale for exploring the use of metformin in the treatment of non-alcoholic fatty liver disease, revealing its blocking effect for hepatic insulin resistance evoked by saturated fatty acids.
Kim
Do-Sung
DS
Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University, Chonbuk, Republic of Korea.
Jeong
Seul-Ki
SK
Kim
Hyung-Ryong
HR
Kim
Dal-Sik
DS
Chae
Soo-Wan
SW
Chae
Han-Jung
HJ
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D047468:Immunoprecipitation; D007328:Insulin / Q000096:biosynthesis; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D018384:Oxidative Stress / Q000187:drug effects*; D019308:Palmitic Acid / Q000009:adverse effects*; D010766:Phosphorylation
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D019308:Palmitic Acid; D008687:Metformin; D053148:Caspase 3