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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 could deteriorate hepatic steatosis in mice exposed to ethanol might be through SRBEP-1c activation. (A) Hepatic TG level; (B) SREBP-1c protein expression in liver determinate by Western blotting; (C) Value of the SREBP-1c protein expression expressed as the folds of control; (D) Hepatic SREBP-1c mRNA level determinate by RT-PCR. Normalizations of Western blots and RT-PCR were ensured by Tubulin or β-actin. Data of A were expressed as mean ± SD (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.
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Figure 7: Insulin pre-administration could deteriorate hepatic steatosis in mice exposed to ethanol might be through SRBEP-1c activation. (A) Hepatic TG level; (B) SREBP-1c protein expression in liver determinate by Western blotting; (C) Value of the SREBP-1c protein expression expressed as the folds of control; (D) Hepatic SREBP-1c mRNA level determinate by RT-PCR. Normalizations of Western blots and RT-PCR were ensured by Tubulin or β-actin. Data of A were expressed as mean ± SD (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: Hepatic steatosis (the accumulation of hepatic triglycerides) is the typical pathological changes and is considered to play a key role in the development of ALD 15. So we next examined the hepatic triglycerides level and the expression of SRBEP-1c, which is an important regulating factor for the process of fat metabolism. As shown in Fig.7 A, insulin administration alone and ethanol exposure could both increase the level of triglycerides in liver, and insulin pre-administration enhanced the increase of hepatic triglycerides level, suggesting insulin pre-administration could deteriorate ethanol-induced hepatic steatosis. As illustrated in Fig.7 B-D, our results revealed that protein and mRNA expressions of SREBP-1c were all up-regulated in insulin group and ethanol group, and as expect, insulin pre-administration further increased the up-regulations of SREBP-1c protein and mRNA expressions in mice exposed to ethanol, suggesting the activation of SREBP-1c might contribute the deteriorative effects of insulin on hepatic steatosis in mice exposed to ethanol.


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 could deteriorate hepatic steatosis in mice exposed to ethanol might be through SRBEP-1c activation. (A) Hepatic TG level; (B) SREBP-1c protein expression in liver determinate by Western blotting; (C) Value of the SREBP-1c protein expression expressed as the folds of control; (D) Hepatic SREBP-1c mRNA level determinate by RT-PCR. Normalizations of Western blots and RT-PCR were ensured by Tubulin or β-actin. Data of A were expressed as mean ± SD (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 7: Insulin pre-administration could deteriorate hepatic steatosis in mice exposed to ethanol might be through SRBEP-1c activation. (A) Hepatic TG level; (B) SREBP-1c protein expression in liver determinate by Western blotting; (C) Value of the SREBP-1c protein expression expressed as the folds of control; (D) Hepatic SREBP-1c mRNA level determinate by RT-PCR. Normalizations of Western blots and RT-PCR were ensured by Tubulin or β-actin. Data of A were expressed as mean ± SD (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: Hepatic steatosis (the accumulation of hepatic triglycerides) is the typical pathological changes and is considered to play a key role in the development of ALD 15. So we next examined the hepatic triglycerides level and the expression of SRBEP-1c, which is an important regulating factor for the process of fat metabolism. As shown in Fig.7 A, insulin administration alone and ethanol exposure could both increase the level of triglycerides in liver, and insulin pre-administration enhanced the increase of hepatic triglycerides level, suggesting insulin pre-administration could deteriorate ethanol-induced hepatic steatosis. As illustrated in Fig.7 B-D, our results revealed that protein and mRNA expressions of SREBP-1c were all up-regulated in insulin group and ethanol group, and as expect, insulin pre-administration further increased the up-regulations of SREBP-1c protein and mRNA expressions in mice exposed to ethanol, suggesting the activation of SREBP-1c might contribute the deteriorative effects of insulin on hepatic steatosis in mice exposed to ethanol.

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