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The effects of insulin pre-administration in mice exposed to ethanol: alleviating hepatic oxidative injury through anti-oxidative, anti-apoptotic activities and deteriorating hepatic steatosis through SRBEP-1c activation.

Liu J, Wang X, Peng Z, Zhang T, Wu H, Yu W, Kong D, Liu Y, Bai H, Liu R, Zhang X, Hai C - Int. J. Biol. Sci. (2015)

Bottom Line: Previous studies have showed that insulin, a classic regulator of glucose metabolism, has significant anti-oxidative function and plays an important role in maintaining the redox balance.First, we found insulin pre-administration alleviated acute ethanol exposure-induced liver injury and inflammation reflected by the decrease of serum AST and ALT activities, the improvement of pathological alteration and the inhibition of TNF-α and IL-6 expressions.Our study provided novel insight about the effects and mechanisms of insulin on ethanol-induced liver injury.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China;

ABSTRACT
Alcoholic liver disease (ALD) has become an important liver disease hazard to public and personal health. Oxidative stress is believed to be responsible for the pathological changes in ALD. Previous studies have showed that insulin, a classic regulator of glucose metabolism, has significant anti-oxidative function and plays an important role in maintaining the redox balance. For addressing the effects and mechanisms of insulin pre-administration on ethanol-induced liver oxidative injury, we investigated histopathology, inflammatory factors, apoptosis, mitochondrial dysfunction, oxidative stress, antioxidant defense system, ethanol metabolic enzymes and lipid disorder in liver of ethanol-exposed mice pretreatment with insulin or not. There are several novel findings in our study. First, we found insulin pre-administration alleviated acute ethanol exposure-induced liver injury and inflammation reflected by the decrease of serum AST and ALT activities, the improvement of pathological alteration and the inhibition of TNF-α and IL-6 expressions. Second, insulin pre-administration could significantly reduce apoptosis and ameliorate mitochondrial dysfunction in liver of mice exposed to ethanol, supporting by decreasing caspases-3 activities and the ratio of Bax/Bcl-2, increasing mitochondrial viability and mitochondrial oxygen consumption, inhibition of the decline of ATP levels and mitochondrial ROS accumulation. Third, insulin pre-administration prevented ethanol-mediated oxidative stress and enhance antioxidant defense system, which is evaluated by the decline of MDA levels and the rise of GSH/GSSG, the up-regulations of antioxidant enzymes CAT, SOD, GR through Nrf-2 dependent pathway. Forth, the modification of ethanol metabolism pathway such as the inhibition of CYP2E1, the activation of ALDH might be involved in the anti-oxidative and protective effects exerted by insulin pre-administration against acute ethanol exposure in mice. Finally, insulin pre-administration deteriorated hepatic steatosis in mice exposed to ethanol might be through SRBEP-1c activation. In summary, these results indicated that insulin pre-administration effectively alleviated liver oxidative injury through anti-inflammatory, anti-oxidative and anti-apoptotic activities but also deteriorated hepatic steatosis through SRBEP-1c activation in mice exposed to ethanol. Our study provided novel insight about the effects and mechanisms of insulin on ethanol-induced liver injury.

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Insulin pre-administration alleviated acute ethanol exposure-induced liver injury and inflammation in mice. (A) H&E staining of liver; (B) ALT and AST level in serum; (C) Hepatic MPO activity; (D) Hepatic TNF-α mRNA level determinate by RT-PCR; (E) Hepatic IL-6 mRNA level determinate by RT-PCR; (F) Serum TNF-α level determinate by ELISA assay; (G) Serum Adiponectin level determinate by ELISA assay. Data of B-C and F-G were expressed as mean ± SD of eight mice per group (n = 8). Data of D and E were expressed as the mean ± SD of three independent experiments (n = 3). *P< 0.05, compared to control group; #P < 0.05, compared to EtOH group.
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Figure 1: Insulin pre-administration alleviated acute ethanol exposure-induced liver injury and inflammation in mice. (A) H&E staining of liver; (B) ALT and AST level in serum; (C) Hepatic MPO activity; (D) Hepatic TNF-α mRNA level determinate by RT-PCR; (E) Hepatic IL-6 mRNA level determinate by RT-PCR; (F) Serum TNF-α level determinate by ELISA assay; (G) Serum Adiponectin level determinate by ELISA assay. Data of B-C and F-G were expressed as mean ± SD of eight mice per group (n = 8). Data of D and E were expressed as the mean ± SD of three independent experiments (n = 3). *P< 0.05, compared to control group; #P < 0.05, compared to EtOH group.

Mentions: To examine whether insulin pre-administration might alleviate liver injury induced by ethanol in mice, the examination of liver histological alterations by Haematoxylin and Eosin Stain, the measurement of ALT and AST activities in serum were conducted. As shown in Fig.1A, ethanol exposure could induce the disordered arrangement of hepatocyte and the swelling of hepatocytes, indicating the typical pathological alterations of ALD. Ethanol induced histopathological disorder was effectively improved by insulin pre-administration. The protective effect of insulin was also confirmed by ALT and AST assay. As illustrated in Fig. 1B, insulin pre-administration significantly alleviated the increase of ALT and AST activities in serum mediated by ethanol exposure. Above results suggested that insulin pre-administration effectively protected the liver against the alcoholic toxicity. To investigate whether insulin pre-administration could alleviate inflammation in liver of mice exposed to ethanol, we next examined the hepatic MPO activity and hepatic mRNA expressions of TNF-α and IL-6. As noted in Fig.1C-E, insulin pre-administration significantly inhibited the increase of MPO activity, gene expressions of TNF-α and IL-6 in liver of mice exposed to ethanol. We next also detected the serum TNF-α level in these mice, the results revealed in Fig.1C showed that insulin pre-administration also alleviated the ethanol-induced high level of serum TNF-α level. As demonstrated in Fig. 1G, insulin administration alone could significantly promote the serum Adiponectin level but ethanol exposure could decline the level of serum Adiponectin, and we found that insulin pre-administration effectively inhibited the decrease of serum Adiponectin level in mice exposed to ethanol. These data indicated that insulin pre-administration had significantly anti-inflammatory effect in ALD.


The effects of insulin pre-administration in mice exposed to ethanol: alleviating hepatic oxidative injury through anti-oxidative, anti-apoptotic activities and deteriorating hepatic steatosis through SRBEP-1c activation.

Liu J, Wang X, Peng Z, Zhang T, Wu H, Yu W, Kong D, Liu Y, Bai H, Liu R, Zhang X, Hai C - Int. J. Biol. Sci. (2015)

Insulin pre-administration alleviated acute ethanol exposure-induced liver injury and inflammation in mice. (A) H&E staining of liver; (B) ALT and AST level in serum; (C) Hepatic MPO activity; (D) Hepatic TNF-α mRNA level determinate by RT-PCR; (E) Hepatic IL-6 mRNA level determinate by RT-PCR; (F) Serum TNF-α level determinate by ELISA assay; (G) Serum Adiponectin level determinate by ELISA assay. Data of B-C and F-G were expressed as mean ± SD of eight mice per group (n = 8). Data of D and E were expressed as the mean ± SD of three independent experiments (n = 3). *P< 0.05, compared to control group; #P < 0.05, compared to EtOH group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4400388&req=5

Figure 1: Insulin pre-administration alleviated acute ethanol exposure-induced liver injury and inflammation in mice. (A) H&E staining of liver; (B) ALT and AST level in serum; (C) Hepatic MPO activity; (D) Hepatic TNF-α mRNA level determinate by RT-PCR; (E) Hepatic IL-6 mRNA level determinate by RT-PCR; (F) Serum TNF-α level determinate by ELISA assay; (G) Serum Adiponectin level determinate by ELISA assay. Data of B-C and F-G were expressed as mean ± SD of eight mice per group (n = 8). Data of D and E were expressed as the mean ± SD of three independent experiments (n = 3). *P< 0.05, compared to control group; #P < 0.05, compared to EtOH group.
Mentions: To examine whether insulin pre-administration might alleviate liver injury induced by ethanol in mice, the examination of liver histological alterations by Haematoxylin and Eosin Stain, the measurement of ALT and AST activities in serum were conducted. As shown in Fig.1A, ethanol exposure could induce the disordered arrangement of hepatocyte and the swelling of hepatocytes, indicating the typical pathological alterations of ALD. Ethanol induced histopathological disorder was effectively improved by insulin pre-administration. The protective effect of insulin was also confirmed by ALT and AST assay. As illustrated in Fig. 1B, insulin pre-administration significantly alleviated the increase of ALT and AST activities in serum mediated by ethanol exposure. Above results suggested that insulin pre-administration effectively protected the liver against the alcoholic toxicity. To investigate whether insulin pre-administration could alleviate inflammation in liver of mice exposed to ethanol, we next examined the hepatic MPO activity and hepatic mRNA expressions of TNF-α and IL-6. As noted in Fig.1C-E, insulin pre-administration significantly inhibited the increase of MPO activity, gene expressions of TNF-α and IL-6 in liver of mice exposed to ethanol. We next also detected the serum TNF-α level in these mice, the results revealed in Fig.1C showed that insulin pre-administration also alleviated the ethanol-induced high level of serum TNF-α level. As demonstrated in Fig. 1G, insulin administration alone could significantly promote the serum Adiponectin level but ethanol exposure could decline the level of serum Adiponectin, and we found that insulin pre-administration effectively inhibited the decrease of serum Adiponectin level in mice exposed to ethanol. These data indicated that insulin pre-administration had significantly anti-inflammatory effect in ALD.

Bottom Line: Previous studies have showed that insulin, a classic regulator of glucose metabolism, has significant anti-oxidative function and plays an important role in maintaining the redox balance.First, we found insulin pre-administration alleviated acute ethanol exposure-induced liver injury and inflammation reflected by the decrease of serum AST and ALT activities, the improvement of pathological alteration and the inhibition of TNF-α and IL-6 expressions.Our study provided novel insight about the effects and mechanisms of insulin on ethanol-induced liver injury.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China;

ABSTRACT
Alcoholic liver disease (ALD) has become an important liver disease hazard to public and personal health. Oxidative stress is believed to be responsible for the pathological changes in ALD. Previous studies have showed that insulin, a classic regulator of glucose metabolism, has significant anti-oxidative function and plays an important role in maintaining the redox balance. For addressing the effects and mechanisms of insulin pre-administration on ethanol-induced liver oxidative injury, we investigated histopathology, inflammatory factors, apoptosis, mitochondrial dysfunction, oxidative stress, antioxidant defense system, ethanol metabolic enzymes and lipid disorder in liver of ethanol-exposed mice pretreatment with insulin or not. There are several novel findings in our study. First, we found insulin pre-administration alleviated acute ethanol exposure-induced liver injury and inflammation reflected by the decrease of serum AST and ALT activities, the improvement of pathological alteration and the inhibition of TNF-α and IL-6 expressions. Second, insulin pre-administration could significantly reduce apoptosis and ameliorate mitochondrial dysfunction in liver of mice exposed to ethanol, supporting by decreasing caspases-3 activities and the ratio of Bax/Bcl-2, increasing mitochondrial viability and mitochondrial oxygen consumption, inhibition of the decline of ATP levels and mitochondrial ROS accumulation. Third, insulin pre-administration prevented ethanol-mediated oxidative stress and enhance antioxidant defense system, which is evaluated by the decline of MDA levels and the rise of GSH/GSSG, the up-regulations of antioxidant enzymes CAT, SOD, GR through Nrf-2 dependent pathway. Forth, the modification of ethanol metabolism pathway such as the inhibition of CYP2E1, the activation of ALDH might be involved in the anti-oxidative and protective effects exerted by insulin pre-administration against acute ethanol exposure in mice. Finally, insulin pre-administration deteriorated hepatic steatosis in mice exposed to ethanol might be through SRBEP-1c activation. In summary, these results indicated that insulin pre-administration effectively alleviated liver oxidative injury through anti-inflammatory, anti-oxidative and anti-apoptotic activities but also deteriorated hepatic steatosis through SRBEP-1c activation in mice exposed to ethanol. Our study provided novel insight about the effects and mechanisms of insulin on ethanol-induced liver injury.

Show MeSH
Related in: MedlinePlus