Limits...
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.

Show MeSH

Related in: MedlinePlus

Insulin pre-administration ameliorated acute ethanol exposure-induced apoptosis in liver of mice. (A) Hepatic Caspase-3 activity; (B) Bcl-2, Bax protein expressions in liver determinate by Western blotting; (C) Values of the Bcl-2, Bax protein expressions expressed as the folds of control; (D) Values of Bax/Bcl-2 expressed as the folds of control. Normalizations of Western blots were ensured by Tubulin. Data of A were expressed as mean ± SD of eight mice per group (n = 8). Data of C and D 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


getmorefigures.php?uid=PMC4400388&req=5

Figure 2: Insulin pre-administration ameliorated acute ethanol exposure-induced apoptosis in liver of mice. (A) Hepatic Caspase-3 activity; (B) Bcl-2, Bax protein expressions in liver determinate by Western blotting; (C) Values of the Bcl-2, Bax protein expressions expressed as the folds of control; (D) Values of Bax/Bcl-2 expressed as the folds of control. Normalizations of Western blots were ensured by Tubulin. Data of A were expressed as mean ± SD of eight mice per group (n = 8). Data of C and D 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 investigate whether insulin pre-administration could alleviate apoptosis in liver of mice exposed to ethanol, we next examined the hepatic caspases-3 activity, protein expressions of hepatic Bcl-2 and Bax. As shown in Fig.2A, obvious increase of hepatic caspases-3 activity was observed in ethanol-treated mice compared with that of control group, while pre-treatment with insulin significantly reduced caspases-3 activity. To confirm the alleviative effects of insulin pre-administration on apoptosis in liver, we then examined the alteration of Bcl-2 and Bax expressions. As illustrated in Fig.2B-D, insulin administration alone had no effects of Bcl-2 and Bax expressions, but insulin pre-administration could effectively blunt the ethanol-induced the down-regulation of Bcl-2 expression, up-regulation of Bax expression and the increase of value of Bax/Bcl-2. These results indicated that insulin pre-administration could protect liver cells from apoptosis in mice suffering ethanol insult, and inhibition of mitochondrial apoptosis pathway might contribute to the insulin pre-administration-induced protective actin in apoptosis.


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 ameliorated acute ethanol exposure-induced apoptosis in liver of mice. (A) Hepatic Caspase-3 activity; (B) Bcl-2, Bax protein expressions in liver determinate by Western blotting; (C) Values of the Bcl-2, Bax protein expressions expressed as the folds of control; (D) Values of Bax/Bcl-2 expressed as the folds of control. Normalizations of Western blots were ensured by Tubulin. Data of A were expressed as mean ± SD of eight mice per group (n = 8). Data of C and D 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 2: Insulin pre-administration ameliorated acute ethanol exposure-induced apoptosis in liver of mice. (A) Hepatic Caspase-3 activity; (B) Bcl-2, Bax protein expressions in liver determinate by Western blotting; (C) Values of the Bcl-2, Bax protein expressions expressed as the folds of control; (D) Values of Bax/Bcl-2 expressed as the folds of control. Normalizations of Western blots were ensured by Tubulin. Data of A were expressed as mean ± SD of eight mice per group (n = 8). Data of C and D 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 investigate whether insulin pre-administration could alleviate apoptosis in liver of mice exposed to ethanol, we next examined the hepatic caspases-3 activity, protein expressions of hepatic Bcl-2 and Bax. As shown in Fig.2A, obvious increase of hepatic caspases-3 activity was observed in ethanol-treated mice compared with that of control group, while pre-treatment with insulin significantly reduced caspases-3 activity. To confirm the alleviative effects of insulin pre-administration on apoptosis in liver, we then examined the alteration of Bcl-2 and Bax expressions. As illustrated in Fig.2B-D, insulin administration alone had no effects of Bcl-2 and Bax expressions, but insulin pre-administration could effectively blunt the ethanol-induced the down-regulation of Bcl-2 expression, up-regulation of Bax expression and the increase of value of Bax/Bcl-2. These results indicated that insulin pre-administration could protect liver cells from apoptosis in mice suffering ethanol insult, and inhibition of mitochondrial apoptosis pathway might contribute to the insulin pre-administration-induced protective actin in apoptosis.

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