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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 reduced ethanol-mediated oxidative stress in liver of mice. (A) Hepatic ROS accumulation in cryosections analyzed by DHE staining using confocal microscopy; (B) Values of hepatic ROS accumulation calculated by DHE fluorescence intensity expressed as the folds of control; (C) Hepatic MDA level; (D) Hepatic GSSG level; (E) Mitochondrial MDA level. Data of B were expressed as the mean ± SD of three independent experiments (n = 3). Data of C-E were expressed as mean ± SD (n = 8). *P< 0.05, compared of control group; #P < 0.05, compared to EtOH group.
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Figure 4: Insulin pre-administration reduced ethanol-mediated oxidative stress in liver of mice. (A) Hepatic ROS accumulation in cryosections analyzed by DHE staining using confocal microscopy; (B) Values of hepatic ROS accumulation calculated by DHE fluorescence intensity expressed as the folds of control; (C) Hepatic MDA level; (D) Hepatic GSSG level; (E) Mitochondrial MDA level. Data of B were expressed as the mean ± SD of three independent experiments (n = 3). Data of C-E were expressed as mean ± SD (n = 8). *P< 0.05, compared of control group; #P < 0.05, compared to EtOH group.

Mentions: To examine whether insulin pre-administration reduced ethanol-mediated oxidative stress, we investigated the hepatic ROS accumulation, hepatic MDA level, hepatic GSSG level and mitochondrial MDA level. As the results determinate by DHE staining using confocal microscopy shown in Fig.4 A and B, there was no significant difference in the changes of hepatic ROS accumulation between insulin administration mice and control mice, and ethanol exposure induced a notable increase of hepatic ROS accumulation, which was significantly alleviated by insulin pre-administration. As noted in Fig.4 C, hepatic MDA level increased significantly in ethanol group compared to the control group, insulin pre-administration reduced MDA to a certain extent toward normal. As illustrated in Fig.4 D, insulin pre-administration markedly inhibited the increase of hepatic GSSG level in ethanol treatment mice. Mitochondrial oxidative damage also played an important role in mitochondrial dysfunction 18. As illustrated in Fig.4 E, the mitochondria from liver of mice treated with ethanol showed increased MDA level compared to control, indicating that ethanol insult resulted in oxidative injury in mitochondria. However, the lower level of mitochondrial MDA in insulin pre-administration mice was detected, which suggested that insulin could notably alleviate the oxidative stress in hepatocytes mitochondria in mice treated with ethanol. These data demonstrated that pre-administration with insulin could effectively reduce ethanol-mediated oxidative stress.


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 reduced ethanol-mediated oxidative stress in liver of mice. (A) Hepatic ROS accumulation in cryosections analyzed by DHE staining using confocal microscopy; (B) Values of hepatic ROS accumulation calculated by DHE fluorescence intensity expressed as the folds of control; (C) Hepatic MDA level; (D) Hepatic GSSG level; (E) Mitochondrial MDA level. Data of B were expressed as the mean ± SD of three independent experiments (n = 3). Data of C-E were expressed as mean ± SD (n = 8). *P< 0.05, compared of control group; #P < 0.05, compared to EtOH group.
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Related In: Results  -  Collection

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

Figure 4: Insulin pre-administration reduced ethanol-mediated oxidative stress in liver of mice. (A) Hepatic ROS accumulation in cryosections analyzed by DHE staining using confocal microscopy; (B) Values of hepatic ROS accumulation calculated by DHE fluorescence intensity expressed as the folds of control; (C) Hepatic MDA level; (D) Hepatic GSSG level; (E) Mitochondrial MDA level. Data of B were expressed as the mean ± SD of three independent experiments (n = 3). Data of C-E were expressed as mean ± SD (n = 8). *P< 0.05, compared of control group; #P < 0.05, compared to EtOH group.
Mentions: To examine whether insulin pre-administration reduced ethanol-mediated oxidative stress, we investigated the hepatic ROS accumulation, hepatic MDA level, hepatic GSSG level and mitochondrial MDA level. As the results determinate by DHE staining using confocal microscopy shown in Fig.4 A and B, there was no significant difference in the changes of hepatic ROS accumulation between insulin administration mice and control mice, and ethanol exposure induced a notable increase of hepatic ROS accumulation, which was significantly alleviated by insulin pre-administration. As noted in Fig.4 C, hepatic MDA level increased significantly in ethanol group compared to the control group, insulin pre-administration reduced MDA to a certain extent toward normal. As illustrated in Fig.4 D, insulin pre-administration markedly inhibited the increase of hepatic GSSG level in ethanol treatment mice. Mitochondrial oxidative damage also played an important role in mitochondrial dysfunction 18. As illustrated in Fig.4 E, the mitochondria from liver of mice treated with ethanol showed increased MDA level compared to control, indicating that ethanol insult resulted in oxidative injury in mitochondria. However, the lower level of mitochondrial MDA in insulin pre-administration mice was detected, which suggested that insulin could notably alleviate the oxidative stress in hepatocytes mitochondria in mice treated with ethanol. These data demonstrated that pre-administration with insulin could effectively reduce ethanol-mediated oxidative stress.

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