Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression.

Abstract

Coenzyme Q10 (CoQ10), an endogenous antioxidant, is important in oxidative phosphorylation in mitochondria. It has anti-diabetic and anti-cardiovascular disease effects, but its ability to protect against liver fibrosis has not been studied. Here, we assessed the ability of solubilized CoQ10 to improve dimethylnitrosamine (DMN)-induced liver fibrogenesis in mice. DMN treatments for 3 weeks produced a marked liver fibrosis as assessed by histopathological examination and tissue 4-hydroxyproline content. Solubilized CoQ10 (10 and 30 mg/kg) significantly inhibited both the increases in fibrosis score and 4-hydroxyproline content induced by DMN. Reverse transcription-polymerase chain reaction and Western blot analyses revealed that solubilized CoQ10 inhibited increases in the transforming growth factor-beta1 (TGF-beta1) mRNA and alpha-smooth muscle actin (alpha-SMA) protein by DMN. Interestingly, hepatic glutamate-cysteine ligase (GCL) and glutathione S-transferase A2 (GSTA2) were up-regulated in mice treated with CoQ10. Solubilized CoQ10 also up-regulated antioxidant enzymes such as catalytic subunits of GCL and GSTA2 via activating NF-E2 related factor2 (Nrf2)/antioxidant response element (ARE) in H4IIE hepatoma cells. Moreover, CoQ10's inhibition of alpha-SMA and TGF-beta1 expressions disappeared in Nrf2-null MEF cells. In contrast, Nrf2 overexpression significantly decreased the basal expression levels of alpha-SMA and TGF-beta1 in Nrf2-null MEF cells. These results demonstrated that solubilized CoQ10 inhibited DMN-induced liver fibrosis through suppression of TGF-beta1 expression via Nrf2/ARE activation.

• Authors: Hoo-Kyun Choi, Yuba Raj Pokharel, Sung Chul Lim, Hyo-Kyung Han, Chang Seon Ryu, Sang Kyum Kim, Mi Kyong Kwak, Keon Wook Kang
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 240 Issue 3 Pg. 377-84 (Nov 01 2009) ISSN: 1096-0333 [Electronic] United States
• PMID: 19647758 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• DNA Primers
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Transforming Growth Factor beta1
• Ubiquinone
• coenzyme Q10

Topics

• Actins (biosynthesis)
• Animals
• Base Sequence
• Cell Line, Tumor
• DNA Primers
• Liver Cirrhosis (metabolism, prevention & control)
• Male
• Mice
• Mice, Inbred ICR
• NF-E2-Related Factor 2 (physiology)
• Rats
• Reverse Transcriptase Polymerase Chain Reaction
• Solubility
• Transforming Growth Factor beta1 (biosynthesis, metabolism)
• Ubiquinone (analogs & derivatives, pharmacology)