HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis.

Abstract
The majority of chronic liver diseases are accompanied by oxidative stress, which induces apoptosis in hepatocytes and liver injury. Recent studies suggest that oxidative stress and insulin resistance are important in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the pathophysiology of diabetes complications. Metformin has been shown to be hepatoprotective in the insulin-resistant and leptin-deficient ob/ob mouse model of NAFLD. However, the mechanism involved in the protective effects of metformin has not been elucidated yet. Therefore, we investigated the protective effect of metformin against oxidative stress-induced apoptosis. Primary rat hepatocytes were exposed to the oxidative stress-generating compound menadione in the presence and absence of metformin. Apoptosis was determined by measuring caspase activity and poly(ADP-ribose) polymerase (PARP)-cleavage, and necrosis was measured by Sytox Green nuclear staining. We demonstrate that (1) Metformin inhibits menadione-induced caspase-9,-6,-3 activation and PARP-cleavage in a concentration-dependent manner. (2) Metformin increases menadione-induced heme oxygenase-1 (HO-1) expression and inhibits c-Jun N-terminal kinase (JNK)-phosphorylation. (3) Metformin does not induce necrosis in primary hepatocytes. Metformin protects hepatocytes against oxidative stress-induced caspase activation, PARP-cleavage and apoptosis. The anti-apoptotic effect of metformin is in part dependent on HO-1 and bcl-xl induction and inhibition of JNK activation and independent of insulin signaling. Our results elucidate novel protective mechanisms of metformin and indicate that metformin could be investigated as a novel therapeutic agent for the treatment of oxidative stress-related liver diseases.
AuthorsLaura Conde de la Rosa, Titia E Vrenken, Manon Buist-Homan, Klaas Nico Faber, Han Moshage
JournalPharmacology research & perspectives (Pharmacol Res Perspect) Vol. 3 Issue 2 Pg. e00125 (Mar 2015) ISSN: 2052-1707 [Print] United States
PMID26038701 (Publication Type: Journal Article)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: