| In our country drinking has a long history, at present, with the increase of people’s socialcommunication and frequent, China has become the country of consumption of alcohol drinks, so in recentyears, the hazards of alcohol on the body have got more and maore concern.The current study found thatchronic alcohol exposure will not only lead to alcoholic liver disease, alcoholic dementia and Alzheimer’sdisease, but also closely related with diabetes, diabetic encephalopathy, and insulin resistance (Insulinresistance, IR). Clinical data show that Type2diabetes associated with IR and nonalcoholic steatohepatitisoften accompanied by varying degrees of cognitive dysfunction, in addition to by alleviating IR, diabetesand Alzheimer’s disease individuals can improve cognitive abilities. In addition, in2009, USAneuropathology expert Suzanne M. de la Monte et al proposed a hypothesis that the live-brain axis ofalcohol-mediated neurodegeneration, it is that alcohol exposure leads to insulin resistance plays the keyrole, ceramide is the bridge between liver and brain, although there is evidence to support the aboveconclusion, but still need further research support and to explore its mechanism. Therefore, we takeadvantage of sphingomyelin synthase2gene knockout (sphingomyelin synthase2knockout, SMS2-/-) willlead to the accumulation of ceramide, and established SMS2-/-mice alcohol exposure model, to observethe effect of ceramide in the live-brain axis of alcohol-mediated neurodegeneration by transmissionelectron microscopy, western blot and immunohistochemistry and other technologies. Analysis relationshipamong ceramide, alcohol and insulin resistance, investigate the effect of ceramide, insulin resistance inalcohol-induced liver and brain axis neurodegenerative,at the same time, providing a theoretical basis.Objective: Our aim is to investigate the relationships among chronic alcohol exposure, insulin sensitivityand ceramide during the alcohol toxicological effects. Our aim is to investigate the relationships among thechronic alcohol exposure, stress injury of liver-brain and ceramide’s effect.Methods: Using wide type (WT) and sphingomyelin synthetase2knockout (SMS2-/-) mice (about3month old) to establish the chronic alcohol exposure models. The two genotypes mice (total90cases) weredivided into the control group, moderate EtOH group and high EtOH group. After alcohol exposure for5months, fasting plasma glucose（FPG）, levels of fasting insulin (Fins) were measured. Then, the insulinresistance index (HOMA-IR) was calculated as well. Then, H.E. staining, Masson staining were carried out on the study to observe liver cells and structural changes. In the meantime, the expression of insulinreceptor substrate2(IRS2) and c-Fos and NF-κB in hippocampus was tested with immunofluorescentlabeling and Western blot analysis.Results:①Alcohol exposure could cause WT mice FPG and HOMA-IR index increased withdose-dependency (P<0.05). Comparing with the control group, Fins values increased in the treatment dosegroup (P <0.05).②FPG in SMS2-/-mice increased with dose-dependency (P<0.05), but HOMA-IR indexhad no too much changes, comparing with WT mice. In addition to, the immunohistochemical stainingshowed that, in both WT and SMS2-/-mice, the number of Positive IRS2cells reduced in CA1area afteralcohol exposure with dose-dependency (P <0.05); However, comParing with the WT mice, the number ofpositive IRS2cells of hippocampus in SMS2-/-mice reduced very much (P<0.05).③Immunoblottingevidence of IRS2supported the data of immunohistochemistry in both in WT and SMS2-/-mice.④Alcoholexposure led to the wild-type and SMS2-/-mice hepatocytic steatosis and hepatic fibrosis. In the meantime,Mallory bodies and inflammatory cell infiltration were found in liver.⑤After alcohol exposure, c-Fos andNF-κB positive cells increased in hippocampal CA1area with dose dependency (P<0.01). However,comparing with the WT pups, the number of positive c-Fos and NF-kB cells in SMS2-/-mice increasedmuch more than WT mice (P<0.05).⑥Immunoblotting evidence of c-Fos and NF-κB protein supportedthe data of immunohistochemistry in both in WT and SMS2-/-mice (P<0.01).Conclusion: Chronic alcohol exposure can cause insulin resistance in the both WT and SMS2-/-mice,IRS2loss probably is one of the causes of insulin resistance in CNS, Oxidative stress and inflammatoryresponses in liver and CNS are the main pathological alterations after chronic alcohol exposure. At thesame time, ceramide may be involved in the reduction of.The alcohol-inducing oxidative stress probably isalso the cause of insulin resistance in organism. Ceramide is involved in the processes of alcohol-mediatedIR and the live-brain axis of alcohol-mediated neurodegeneration. That is, alcohol exposure induces theoxidative stress injury in liver-brain axis, such as inflammatory responses and the expression of oxidativestress cues. Ceramide increases the alterations above. |
PDF Full Text Request