Metformin administration induces hepatotoxic effects in paraoxonase-1-deficient mice. (5th April 2016)

• Record Type: Journal Article
• Authors: García-Heredia, Anabel; Riera-Borrull, Marta; Fort-Gallifa, Isabel; Luciano-Mateo, Fedra; Cabré, Noemí; Hernández-Aguilera, Anna; Joven, Jorge; Camps, Jordi
• Is Part Of: Chemico-biological interactions. Volume 249(2016)
• Page Start: 56
• Page End: 63
• Publication Date: 2016-04-05
• Subjects: Antioxidants -- Hepatotoxicity -- Inflammation -- Metformin -- NAFLD -- Paraoxonase -- Steatosis; ALT Alanine aminotransferase -- AMPK Adenosine monophosphate-activated protein kinase -- AST Aspartate aminotransferase -- BAT Brown adipose tissue -- CD Chow diet -- eWAT Epididimal white adipose tissue -- FASn Fatty acid synthase -- FPLC Fast protein liquid chromatography -- GTT Glucose tolerance test -- HDL High-density lipoproteins -- HFD High-fat and high-cholesterol diet -- iWAT Inguinal white adipose tissue -- CCL2 Chemokine (C–C motif) ligand-2 -- pAMPK Phosphorylated AMPK -- PON1 Paraoxonase-1 -- vWAT Visceral white adipose tissue; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2016.03.004
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Metformin is the first-line pharmacological treatment of diabetes. In these patients, metformin reduces body weight and decreases the risk of diabetes-related complications such as cardiovascular disease. However, whether metformin elicits beneficial effects on liver histology is a controversial issue and, as yet, there is no consensus. Paraoxonase-1 (PON1), an enzyme synthesized mainly by the liver, degrades lipid peroxides and reduces oxidative stress. PON1 activities are decreased in chronic liver diseases. We evaluated the effects of metformin in the liver of PON1-deficient mice which, untreated, present a mild degree of liver steatosis. Metformin administration aggravated inflammation in animals given a standard mouse chow and in those fed a high-fat diet. Also, it was associated with a higher degree of steatosis in animals fed a standard chow diet. This report is a cautionary note regarding the prescription of metformin for the treatment of diabetes in patients with concomitant liver impairment. Highlights: Studies have reported toxic effects of metformin in patients with liver disease. PON1 is an antioxidant enzyme synthesized mainly by the liver. We found that metformin administration increases steatosis and inflammation in PON1-deficient mice. PON1 deficiency is associated with toxic effects of metformin in the liver.