Lycopene Antagonizes DEHP Induced Hepatotoxicity By Regulating Lipid Metabolism

Di(2-ethylhexyl)phthalate(DEHP)is a widespread environmental pollutant,which seriously affects human and animal health,thereby disturbing the stability of the ecosystem.Lycopene(LYC)is a dietary supplement with effective antioxidant and anti-obesity functions.Hypoxia-inducible factor-1α(HIF-1α)is a regulator of intracellular hypoxia response and plays a key role in regulating liver lipid metabolism and glucose metabolism.Farnesol derivative X receptor(FXR),liver X receptor(LXR),peroxisome proliferator activated receptor α/γ(PPARα/γ),these nuclear receptors synthesize and transport liver lipoproteins,Denaturation and metabolism are closely related.The purpose of this study is to explore the molecular mechanism of LYC inhibiting DEHP-induced liver lipid metabolism.In this experiment,male ICR mice were used as the test subjects.DEHP and LYC were administered continuously for 28 days to observe the overall state of the mice and liver pathological changes,and detect liver function,the expression of related transcription factors and corresponding receptors in HIF-1α and FXR/LXR/PPARα/PPARγsignaling pathways.The results show:(1)LYC can inhibit the damage of liver function caused by DEHP,alleviate histopathological damage(increased liver sinusoid space,blurred liver lobule structure,disorganized arrangement and dissolution of nuclei,fatty degeneration in liver cells).LYC antagonizes DEHP-induced liver toxicity by regulating the lipid metabolic indexes(T-CHO,TG,NEFA,and LPS)of liver tissue.(2)LYC regulates its downstream target genes(EPO,LDH-A,ET-1,VEGF,Flk-1,b FGF,Glut1,pdk1,l1 cam,Flt1)by regulating the levels of HIF-1α,and then antagonize the abnormal nuclear receptor response induced by DEHP.(3)LYC regulates LXR downstream target genes(ABCA1,ACACA,ACACB,ACLY)and FXR downstream target genes(BESP,FGF14,SHP,SLC51 A,SLC51B,NTCP)expression,thereby inhibiting DEHP exposure and destroying lipid metabolism in liver tissues,eventually reducing liver damage.(4)LYC regulates the expression of PPARα and PPARγ genes,total protein and nucleoprotein,and improves the downstream related factors of lipoprotein synthesis(APOA1,APOA2,APOC3,APOA4 and APOA5)and ketogenesis in lipid metabolism.Related genes(HMGCS2),new fat formation related genes(ELOVL6,FASN,SREBP1 and THRSP),cholesterol metabolism related genes(CYP7A1,CYP8A1,CYP27A1,HSD3B7 and AKR1D1)and fatty acid transport related genes(ACBP,FABP1,ACS,FATP 1and FATP4),fatty acid oxidation-related genes(SCP-X,ACADL,ACOX1,CPT1 A,CPT2,ECH1,MCAD,HADHA,and EHHADH)and lipid droplet-related genes(ADFP,PLIN4,and LPL),thereby inhibiting the expression of DEHP-induced lipid metabolism disorders in the liver of mice.In summary,LYC can improve DEHP-induced liver lipid metabolism disorder by inhibiting the HIF-1α-mediated FXR/LXR/PPARα/PPARγ system.