Limits...
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.

Show MeSH

Related in: MedlinePlus

CYP2E1 inhibition by CMZ completely blocked chronic ethanol-induced lipid accumulation in mice liver.Mice were treated with liquid diet with or without ethanol in the presence/absence of CMZ for 4 weeks. (a) H&E staining; (b) Sudan III staining; (c) Oil red O staining; (d) Ultrastructural examination.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4043914&req=5

pone-0098658-g002: CYP2E1 inhibition by CMZ completely blocked chronic ethanol-induced lipid accumulation in mice liver.Mice were treated with liquid diet with or without ethanol in the presence/absence of CMZ for 4 weeks. (a) H&E staining; (b) Sudan III staining; (c) Oil red O staining; (d) Ultrastructural examination.

Mentions: As shown in Table 2, significant increase of the serum TG level, hepatic TG level, liver index, and ALT and AST activities were observed in ethanol group mice. However, CMZ co-treatment suppressed the increase of the above parameters except the liver index (the liver weight/body weight ×100%), which indicated the amelioration of ethanol-induced liver damage by CMZ. Liver pathological examination was also performed to investigate hepatic fat accumulation in mice liver (Fig. 2). H&E staining showed massive microvesicular steatosis in ethanol group mice liver, which was obviously alleviative in CMZ/ethanol group mice liver (Fig. 2a). The results of the fat specific staining, Sudan III and oil red O staining, showed massive yellow- or red-stained lipid droplets in liver sections of ethanol group mice, while no obvious fat droplets were presented in the liver sections of CMZ/ethanol group mice (Fig. 2b&2c). The ultrastructural examination further demonstrated CYP2E1 inhibition by CMZ suppressed chronic ethanol-induced fat accumulation in mice liver (Fig. 2d).


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)

CYP2E1 inhibition by CMZ completely blocked chronic ethanol-induced lipid accumulation in mice liver.Mice were treated with liquid diet with or without ethanol in the presence/absence of CMZ for 4 weeks. (a) H&E staining; (b) Sudan III staining; (c) Oil red O staining; (d) Ultrastructural examination.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098658-g002: CYP2E1 inhibition by CMZ completely blocked chronic ethanol-induced lipid accumulation in mice liver.Mice were treated with liquid diet with or without ethanol in the presence/absence of CMZ for 4 weeks. (a) H&E staining; (b) Sudan III staining; (c) Oil red O staining; (d) Ultrastructural examination.
Mentions: As shown in Table 2, significant increase of the serum TG level, hepatic TG level, liver index, and ALT and AST activities were observed in ethanol group mice. However, CMZ co-treatment suppressed the increase of the above parameters except the liver index (the liver weight/body weight ×100%), which indicated the amelioration of ethanol-induced liver damage by CMZ. Liver pathological examination was also performed to investigate hepatic fat accumulation in mice liver (Fig. 2). H&E staining showed massive microvesicular steatosis in ethanol group mice liver, which was obviously alleviative in CMZ/ethanol group mice liver (Fig. 2a). The results of the fat specific staining, Sudan III and oil red O staining, showed massive yellow- or red-stained lipid droplets in liver sections of ethanol group mice, while no obvious fat droplets were presented in the liver sections of CMZ/ethanol group mice (Fig. 2b&2c). The ultrastructural examination further demonstrated CYP2E1 inhibition by CMZ suppressed chronic ethanol-induced fat accumulation in mice liver (Fig. 2d).

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