Metformin inhibits expression of the proinflammatory biomarker inducible nitric oxide synthase in hepatocytes

Richi Nakatake, Hiroya Iida, Morihiko Ishizaki, Kosuke Matsui, Yusuke Nakamura, Masaki Kaibori, Mikio Nishizawa, Tadayoshi Okumura

Abstract


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 


Full Text: [Abstract] [Full Article]

DOI: 10.31989/ffhd.v8i3.423

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