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CMZ reversed chronic ethanol-induced disturbance of PPAR-α possibly by suppressing oxidative stress and PGC-1α acetylation, and activating the MAPK and GSK3β pathway.

Zeng T, Zhang CL, Song FY, Zhao XL, Xie KQ - PLoS ONE (2014)

Bottom Line: Chronic ethanol exposure led to significant decrease of the mRNA and protein levels of peroxisome proliferator-activated receptor α (PPAR-α), which was blocked by CMZ co-treatment.CMZ co-treatment suppressed ethanol-induced oxidative stress, overproduction of tumor necrosis α (TNF-α), and decrease of protein levels of the PPAR-α co-activators including p300 and deacetylated PGC1-α.These results suggested that CMZ suppressed chronic ethanol-induced oxidative stress, TNF-α overproduction, decline of p300 protein level and deacetylation of PGC1-α, and activated AMPK, MAPK, and PI3K/Akt/GSK3β pathway, which might contribute to the activation of PPAR-α and account for the protection of CMZ against AFL.

View Article: PubMed Central - PubMed

Affiliation: Institute of Toxicology, School of Public Health, Shandong University, Jinan City, Shandong Province, People's Republic of China.

ABSTRACT

Background: Cytochrome P4502E1 (CYP2E1) has been suggested to play critical roles in the pathogenesis of alcoholic fatty liver (AFL), but the underlying mechanisms remains unclear. The current study was designed to evaluate whether CYP2E1 suppression by chlormethiazole (CMZ) could suppress AFL in mice, and to explore the underlying mechanisms.

Methods: Mice were treated with or without CMZ (50 mg/kg bw, i.p.) and subjected to liquid diet with or without ethanol (5%, w/v) for 4 weeks. Biochemical parameters were measured using commercial kits. The protein and mRNA levels were detected by western blot and qPCR, respectively. Histopathology and immunohistochemical assay were performed with routine methods.

Results: CYP2E1 inhibition by CMZ completely blocked AFL in mice, shown as the decline of the hepatic and serum triglyceride levels, and the fewer fat droplets in the liver sections. Chronic ethanol exposure led to significant decrease of the mRNA and protein levels of peroxisome proliferator-activated receptor α (PPAR-α), which was blocked by CMZ co-treatment. CMZ co-treatment suppressed ethanol-induced oxidative stress, overproduction of tumor necrosis α (TNF-α), and decrease of protein levels of the PPAR-α co-activators including p300 and deacetylated PGC1-α. Furthermore, CMZ co-treatment led to the activation of AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), and PI3K/Akt/GSK3β pathway. However, chronic ethanol-induced decline of acyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) protein levels was partially restored by CMZ, while the activation of autophagy appeared to be suppressed by CMZ.

Conclusion: These results suggested that CMZ suppressed chronic ethanol-induced oxidative stress, TNF-α overproduction, decline of p300 protein level and deacetylation of PGC1-α, and activated AMPK, MAPK, and PI3K/Akt/GSK3β pathway, which might contribute to the activation of PPAR-α and account for the protection of CMZ against AFL.

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A possible scheme for the protective effects of CMZ against chronic ethanol-induced fatty liver.Ethanol-induced CYP2E1 activation can lead to the suppression of PPAR-α, which may be related with the decline of the p300 protein level, the increase of PGC-1α acetylation, and the disturbance of several protein kinases including AMPK, MAPK, and GSK3β. CYP2E1 activation can also result in oxidative stress, which will lead to the overproduction of TNF-α by activating kupffer cells. In contrast, the protective effects of CMZ against AFL might not be associated with the SREBP-1 mediated lipogenesis and autophagy pathway, which are needed to be confirmed in future studies.
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pone-0098658-g011: A possible scheme for the protective effects of CMZ against chronic ethanol-induced fatty liver.Ethanol-induced CYP2E1 activation can lead to the suppression of PPAR-α, which may be related with the decline of the p300 protein level, the increase of PGC-1α acetylation, and the disturbance of several protein kinases including AMPK, MAPK, and GSK3β. CYP2E1 activation can also result in oxidative stress, which will lead to the overproduction of TNF-α by activating kupffer cells. In contrast, the protective effects of CMZ against AFL might not be associated with the SREBP-1 mediated lipogenesis and autophagy pathway, which are needed to be confirmed in future studies.

Mentions: In summary, the current study demonstrated that CYP2E1 suppression by CMZ completely blocked chronic ethanol-induced fatty liver in mice treated with Lieber-DeCarli liquid diet (containing 5% ethanol). CMZ co-treatment significantly inhibited chronic ethanol-induced oxidative stress and the overproduction of TNF-α, and suppressed chronic ethanol-induced decrease of p300 protein level and Sirt-1 mediated deacetylation of PGC-1α. Furthermore, CMZ co-treatment also led to the activation of MAPK (Erk1/2 and p38MAPK) and PI3K/Akt/GSK3β pathway. These factors synergistically led to the stability and the transcriptional activation of PPAR-α, and contributed to the protective effects of CMZ against AFL. In contrast, the SREBP-1 mediated fatty acid synthesis pathway and autophagy associated lipid decomposition might be not involved in the protective effects of CMZ. (Fig.11)


CMZ reversed chronic ethanol-induced disturbance of PPAR-α possibly by suppressing oxidative stress and PGC-1α acetylation, and activating the MAPK and GSK3β pathway.

Zeng T, Zhang CL, Song FY, Zhao XL, Xie KQ - PLoS ONE (2014)

A possible scheme for the protective effects of CMZ against chronic ethanol-induced fatty liver.Ethanol-induced CYP2E1 activation can lead to the suppression of PPAR-α, which may be related with the decline of the p300 protein level, the increase of PGC-1α acetylation, and the disturbance of several protein kinases including AMPK, MAPK, and GSK3β. CYP2E1 activation can also result in oxidative stress, which will lead to the overproduction of TNF-α by activating kupffer cells. In contrast, the protective effects of CMZ against AFL might not be associated with the SREBP-1 mediated lipogenesis and autophagy pathway, which are needed to be confirmed in future studies.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043914&req=5

pone-0098658-g011: A possible scheme for the protective effects of CMZ against chronic ethanol-induced fatty liver.Ethanol-induced CYP2E1 activation can lead to the suppression of PPAR-α, which may be related with the decline of the p300 protein level, the increase of PGC-1α acetylation, and the disturbance of several protein kinases including AMPK, MAPK, and GSK3β. CYP2E1 activation can also result in oxidative stress, which will lead to the overproduction of TNF-α by activating kupffer cells. In contrast, the protective effects of CMZ against AFL might not be associated with the SREBP-1 mediated lipogenesis and autophagy pathway, which are needed to be confirmed in future studies.
Mentions: In summary, the current study demonstrated that CYP2E1 suppression by CMZ completely blocked chronic ethanol-induced fatty liver in mice treated with Lieber-DeCarli liquid diet (containing 5% ethanol). CMZ co-treatment significantly inhibited chronic ethanol-induced oxidative stress and the overproduction of TNF-α, and suppressed chronic ethanol-induced decrease of p300 protein level and Sirt-1 mediated deacetylation of PGC-1α. Furthermore, CMZ co-treatment also led to the activation of MAPK (Erk1/2 and p38MAPK) and PI3K/Akt/GSK3β pathway. These factors synergistically led to the stability and the transcriptional activation of PPAR-α, and contributed to the protective effects of CMZ against AFL. In contrast, the SREBP-1 mediated fatty acid synthesis pathway and autophagy associated lipid decomposition might be not involved in the protective effects of CMZ. (Fig.11)

Bottom Line: Chronic ethanol exposure led to significant decrease of the mRNA and protein levels of peroxisome proliferator-activated receptor α (PPAR-α), which was blocked by CMZ co-treatment.CMZ co-treatment suppressed ethanol-induced oxidative stress, overproduction of tumor necrosis α (TNF-α), and decrease of protein levels of the PPAR-α co-activators including p300 and deacetylated PGC1-α.These results suggested that CMZ suppressed chronic ethanol-induced oxidative stress, TNF-α overproduction, decline of p300 protein level and deacetylation of PGC1-α, and activated AMPK, MAPK, and PI3K/Akt/GSK3β pathway, which might contribute to the activation of PPAR-α and account for the protection of CMZ against AFL.

View Article: PubMed Central - PubMed

Affiliation: Institute of Toxicology, School of Public Health, Shandong University, Jinan City, Shandong Province, People's Republic of China.

ABSTRACT

Background: Cytochrome P4502E1 (CYP2E1) has been suggested to play critical roles in the pathogenesis of alcoholic fatty liver (AFL), but the underlying mechanisms remains unclear. The current study was designed to evaluate whether CYP2E1 suppression by chlormethiazole (CMZ) could suppress AFL in mice, and to explore the underlying mechanisms.

Methods: Mice were treated with or without CMZ (50 mg/kg bw, i.p.) and subjected to liquid diet with or without ethanol (5%, w/v) for 4 weeks. Biochemical parameters were measured using commercial kits. The protein and mRNA levels were detected by western blot and qPCR, respectively. Histopathology and immunohistochemical assay were performed with routine methods.

Results: CYP2E1 inhibition by CMZ completely blocked AFL in mice, shown as the decline of the hepatic and serum triglyceride levels, and the fewer fat droplets in the liver sections. Chronic ethanol exposure led to significant decrease of the mRNA and protein levels of peroxisome proliferator-activated receptor α (PPAR-α), which was blocked by CMZ co-treatment. CMZ co-treatment suppressed ethanol-induced oxidative stress, overproduction of tumor necrosis α (TNF-α), and decrease of protein levels of the PPAR-α co-activators including p300 and deacetylated PGC1-α. Furthermore, CMZ co-treatment led to the activation of AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), and PI3K/Akt/GSK3β pathway. However, chronic ethanol-induced decline of acyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) protein levels was partially restored by CMZ, while the activation of autophagy appeared to be suppressed by CMZ.

Conclusion: These results suggested that CMZ suppressed chronic ethanol-induced oxidative stress, TNF-α overproduction, decline of p300 protein level and deacetylation of PGC1-α, and activated AMPK, MAPK, and PI3K/Akt/GSK3β pathway, which might contribute to the activation of PPAR-α and account for the protection of CMZ against AFL.

Show MeSH
Related in: MedlinePlus