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Metformin inhibits expression of the proinflammatory biomarker inducible nitric oxide synthase in hepatocytes
Author(s) -
Richi Nakatake,
Hiroya Iida,
Morihiko Ishizaki,
Kosuke Matsui,
Yusuke Nakamura,
Masaki Kaibori,
Mikio Nishizawa,
Tadayoshi Okumura
Publication year - 2018
Publication title -
functional foods in health and disease/journal of functional foods in health and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.275
H-Index - 18
eISSN - 2378-7007
pISSN - 2160-3855
DOI - 10.31989/ffhd.v8i3.423
Subject(s) - metformin , nitric oxide synthase , proinflammatory cytokine , tumor necrosis factor alpha , nitric oxide , pharmacology , endocrinology , liver injury , medicine , chemistry , inflammation , diabetes mellitus
Background: Metformin is used to treat patients with type II diabetes. However, there are few scientific reports on its anti-inflammatory effects. In the inflamed liver, proinflammatory cytokines stimulate liver cells, followed by inducible nitric oxide synthase (iNOS) expression. Excessive NO levels produced by iNOS have been implicated as a factor in liver injury. As a result, it is essential to inhibit iNOS induction to prevent liver injury.Objective: This study aimed to investigate liver protective effects of metformin by examining interleukin (IL)-1β-stimulated hepatocytes. Methods: Primary cultured rat hepatocytes were treated with interleukin (IL)-1β in the presence or absence of metformin. iNOS induction and its signaling pathway were analyzed.Results: Metformin decreased iNOS protein and mRNA expression, resulting in the inhibition of hepatic NO production. Metformin also reduced tumor necrosis factor (TNF)-α and IL-6 mRNA expression. Metformin inhibited an essential signaling pathway for iNOS induction, type I IL-1 receptor upregulation. Transfection experiments revealed that metformin reduced iNOS mRNA levels through both promoter transactivation and mRNA stabilization. Delayed metformin administration after IL-1β addition also inhibited iNOS induction. Conclusions: Metformin affects the induction of inflammatory mediators including iNOS and TNF-α, demonstrating its therapeutic potential for organ injuries, including the liver.Keywords: metformin, inducible nitric oxide synthase, liver injury, primary cultured hepatocytes, type I interleukin-1 receptor, tumor necrosis factor-α

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