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

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.

SIRT1 exhibits antioxidative effects in HT22 cells induced by tert‐butyl alcohol

“…These findings indicate that TBA has oxidative activities through direct ROS generating and suppressing the activities of endogenous antioxidant enzymes. Similar changes in free radical and endogenous antioxidant enzyme levels were found in alcoholic liver disease, reperfusion injury of rat retina and the patients undergoing open heart surgery with cardiopulmonary bypass …”

Schisandra sphenanthera extract (Wuzhi Tablet) protects against chronic-binge and acute alcohol-induced liver injury by regulating the NRF2-ARE pathway in mice

“…Specifically, CYP2E1 metabolizes ethanol and generates ROS in this process. Meanwhile, ethanol itself can induce CYP2E1 expression, which further exacerbates this oxidative stress 36 . Hence inhibition of ethanol-induced expression of CYP2E1 and oxidative stress may be crucial to protect against alcoholic liver disease.…”

Is Liver Enzyme Release Really Associated with Cell Necrosis Induced by Oxidant Stress?

“…Thereby, hepatic steatosis is the early manifestation of alcohol liver disease (ALD) and is believed to be the fundamental pathological change of other more severe alcoholic liver diseases [ 32 ]. In addition, insulin pretreatment could exert a significant protective effect on oxidative damage and inflammatory reaction in the liver against ethanol exposure, but insulin can also exacerbate hepatic steatosis in mice exposed to ethanol [ 33 ]. Fatty acid synthesis in liver is mainly regulated by sterol regulatory elements binding protein-1c (SREBP-1c).…”

“…Insulin could also lead to the activation of SREBP-1c to increase the triglycerides in hepatocytes [ 35 ]. Indeed the expression of SREBP-1c can be regulated upwards by the administration of insulin and ethanol, suggesting that SREBP-1c activation might contribute to the deteriorative effects of insulin preadministration on hepatic steatosis in mice exposed to ethanol [ 33 ]. According to the “two-hit” hypothesis for ALD, even though steatosis is reversible, it might be the basis of other serious liver diseases and pathologies including steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma [ 32 ].…”