| To date,the highly active anti-retroviral therapy(HAART)treatment is still the most effective way to control human immunodeficiency virus(HIV)which cannot be completely resolved,a lot of side effects come along with its lifelong medication requirement,causing damages to the patient's heart,nerves,kidneys,metabolism,and other systems and organs.Dyslipidemia is one of the most common side effects of HAART,inducing or promoting various inflammations response in HIV patients.Based on the above,we tried to regulate the dyslipidemia and the ulcerative colitis(UC)which is the HIV common complication,with the efavirenz(EF V)(an anti-retroviral therapy(ART)treatment efavirenz(EFV)).We had researched the effect of EFV on dyslipidemia and UC both in vitro and vivo,starting with 7-Dehydrocholesterol reductase(DHCR7)and its substrate 7-Dehydrocholesterol(7-DHC)in the cholesterol synthesis pathway,and observed the mechanism of 7-DHC inducing serine/threonine kinase(Akt)and inducible Nitric Oxide Synthase(iNOS)under different lipid conditions.Palmitic acid(PA)had been used to simulate the dyslipidemia environment with human normal intestinal epithelial mucosal cells(FHC)in vitro.And small interfering RNA(siRNA)and lentiviral overexpression system were constructed to study the mechanism of DHCR7 with dyslipidemia and its relative inflammations.At the same time,we constructed the dyslipidemia model in SD rats with high fat diet(HFD)and provided the ART treatment for observing the effect of ART on HFD induced dyslipidemia in vivo.The UC model was induced by DSS after 10 weeks ART treatment,studying the relationship and possible mechanism between dyslipidemia and UC.Meantime,16S rDNA detection was provided to analyze the effects of ART treatment on the gut microbiota of rats,fecal microbiota transplantation(FMT)was used to investigate the potential mechanism of EFV mediating regulation between the dyslipidemia and UC.EFV treated rats were founded to be shown the effect of ameliorating the dyslipidemia and UC.Meantime,the inflammatory response of FHC cells induced by PA in vitro showed that DHCR7 can be inhibited by the PA.With the result of 7-DHC content detection,the inflammatory response caused by high-fat culture environment to FHC cells might be induced by the 7-DHC,which could activate the phosphorylation of Akt and upregulate the expression of inflammatory factors.We also found that ART treatment had no significant effect on the expression of DHCR7,SREBP1 and SREBP2 in FHC cells,and cannot alleviate the inflammatory response induced by PA in vitro.The vivo experiment showed that EFV could ameliorate the HFD induced dyslipidemia,and relieve the dyslipidemia promoted symptoms of UC.The gut microbiota of the rats that had taken EFV showed the same ability of resisting dyslipidemia and alleviating the exacerbation of UC in the rats after FMT.The down-regulation effect of DHCR7 and the accumulation of 7-DHC were also found to be ameliorated by the EFV treatment,which also reduced the Akt phosphorylation and the expression of related inflammatory factors.In FMT experiment in rats,we revealed that the microbiota of rats that had taken EFV can alleviate HFD-induced dyslipidemia.The downregulation of DHCR7 expression and accumulation of 7-DHC caused by dyslipidemia could be relieved with the EFV related microbiota,the Akt phosphorylation and the activation of inflammation-related pathways could also be ameliorated with it,EFV related microbiota also reduced the up-regulation of pro-inflammatory cytokine expression.In summary,for ART-induced dyslipidemia,we have discovered the potential mechanism of EFV in the regulation of blood lipids,and found that EFV can alleviate the exacerbation of UC.At the same time,the gut microbiota played an important role in the HAART with our results.With the discovery of microbiota that promoting lipid metabolism,in sight of prospective,we might be able to provide patients with corresponding microbiota therapy by using FMT or probiotics in ART induced dyslipidemia. |
PDF Full Text Request