MilliporeSigma
  • Involvement of insulin resistance in the protective effect of metformin against alcoholic liver injury.

Involvement of insulin resistance in the protective effect of metformin against alcoholic liver injury.

Alcoholism, clinical and experimental research (2014-05-07)
ZhanTao Zhu, ZhiAn Jiang, JunYing Zhou, DongFang Zhou, Wei Wang, CaiYan Zhao, Zhen Zhen, Amin A Nanji
ABSTRACT

Alcoholic liver disease (ALD) continues to be a major cause of morbidity worldwide. The exact mechanisms for ALD pathogenesis are not fully understood. There is currently no known available drug for ALD. Previous studies have suggested that ethanol (EtOH)-induced hepatic insulin resistance, through the inhibition of adenosine monophosphate-activated protein kinase (AMPK) and the expression of adiponectin as well as downstream enzymes, contribute to the development of ALD. This study was to determine the effects of EtOH on AMPK activity as well as the protective effect of metformin. Forty male Wistar rats weighing 200 ± 20 g were randomized into 4 groups (n = 10) as follows: A = control group-rats received rodent chow; B = control + metformin group-rats received metformin (200 mg/kg/d intragastrically [IG]) at 21:00; C = EtOH group-rats were gavaged with alcohol of gradually increasing concentrations (30 to 60%, 5 to 9 g/kg/d) twice a day (9:00 and 16:00); D = EtOH + metformin group-rats received the same amount of EtOH as the rats in group C, and in addition received metformin (200 mg/kg/d IG) at 21:00. After 16 weeks, blood and liver samples were collected for further study. Chronic EtOH consumption led to liver injury both histologically and biochemically accompanied by insulin resistance, reduced AMPK activity, and dysregulation of downstream enzymes. Decreased levels of circulating adiponectin and decreased expression of proliferator-activated receptor gamma coactivator-1α (PGC-1α) and peroxisome proliferator-activated receptors-α (PPAR-α) in the hepatic tissue were observed. Treatment with metformin attenuated the severity of liver injury, restored AMPK activity and normalized the expression of acetyl-CoA carboxylase and fatty acid synthase. In addition, metformin also increased the circulating adiponectin and liver adiponectin receptor 2 expression. Furthermore, PGC-1α and PPAR-α activities were also restored. EtOH exposure induces hepatic insulin resistance. Metformin improved insulin resistance and reversed liver injury through the activation of AMPK and normalized adiponectin signaling making metformin a promising drug for the treatment of ALD.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Mouse IL-6 R ELISA Kit, for serum, plasma and cell culture supernatant
Sigma-Aldrich
Rat IL-6 ELISA Kit, for serum, plasma and cell culture supernatants
Sigma-Aldrich
Rat Interleukin-6 ELISA Kit, for for cell lysate and tissue lysate
Supelco
L-Threonine, Pharmaceutical Secondary Standard; Certified Reference Material
Serine, European Pharmacopoeia (EP) Reference Standard
SAFC
HEPES
SAFC
HEPES
Supelco
HEPES, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
HEPES, anhydrous, free-flowing, Redi-Dri, ≥99.5%
Tyrosine, European Pharmacopoeia (EP) Reference Standard
L-Threonine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
HEPES buffer solution, 1 M in H2O
Supelco
L-Threonine, certified reference material, TraceCERT®, Manufactured by: Sigma-Aldrich Production GmbH, Switzerland
Sigma-Aldrich
HEPES, BioUltra, for molecular biology, ≥99.5% (T)
Sigma-Aldrich
L-Threonine, BioXtra, ≥99.5% (NT)
SAFC
L-Threonine
Sigma-Aldrich
HEPES, BioPerformance Certified, ≥99.5% (titration), suitable for cell culture
Sigma-Aldrich
HEPES, BioXtra, suitable for mouse embryo cell culture, ≥99.5% (titration)
Sigma-Aldrich
HEPES, BioXtra, pH 5.0-6.5 (1 M in H2O), ≥99.5% (titration)
Sigma-Aldrich
HEPES, ≥99.5% (titration)
Sigma-Aldrich
L-Threonine, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, 99.0-101.0%
Sigma-Aldrich
L-Threonine, reagent grade, ≥98% (HPLC)
Sigma-Aldrich
Mouse IL-6 ELISA Kit, for serum, plasma and cell culture supernatant
Sigma-Aldrich
Mouse IL-6 ELISA Kit, for cell and tissue lysates
Sigma-Aldrich
DL-Tyrosine, 99%
Sigma-Aldrich
β-D-Allose, rare aldohexose sugar
Sigma-Aldrich
DL-Serine, ≥98% (TLC)
Sigma-Aldrich
DL-Serine, BioReagent, suitable for cell culture, suitable for insect cell culture, ≥98% (HPLC)