Lycopene Inhibits Cholesterol Absorption Through PPARγ-LXRα-NPC1L1 Signaling Pathway In Caco-2 Cells

backgroundHypercholesterolemia is one of the main risk factors of atherosclerotic heart disease and its occurrence is closely related to daily diet.In recent years,with the change of people’s lifestyle and dietary surplus,the number of patients with hypercholesterolemia has increased year by year,and the incidence of atherosclerotic cardiovascular disease has also increased year by year,and has a younger trend.Therefore,it is of great scientific significance to study the effect of natural cholesterol-lowering substances in food and clarify its molecular mechanism for the prevention and treatment of hypercholesterolemia and related cardiovascular diseases.As a natural phytochemical,lycopene exists widely in tomato,watermelon and other vegetables and fruits,and has a variety of biological activities such as anti-oxidation and anti-inflammation.In recent years,the effect of lycopene on improving blood lipids and inhibiting cardiovascular disease has also attracted the attention of many scholars,but the mechanism of lycopene inhibiting cholesterol absorption is not clear.NPC1L1 is a key transporter mediating intestinal cholesterol absorption,and its expression is regulated by upstream nuclear receptor transcription factors such as PPAR and LXR.Studies have shown that lycopene can affect the function of many transcription factors,but whether lycopene can regulate the expression of NPC1L1 through PPAR and LXR nuclear receptor signal pathways to regulate cholesterol absorption is not clear,all of which need to be further studied.MethodsIn this study,we established Caco2 cells as a model of intestinal epithelial cells to study the effect of lycopene on cholesterol absorption.The amount of[14C]-cholesterol uptake was measured by liquid scintillation counter,and the expression of cholesterol absorption transporter Niemann-pick C1-like protein 1(NPC1L1),peroxisome proliferator-activated receptor gamma(PPAR y)and liver X receptor α(LXR α)were detected by real-time quantitative PCR and Western blot after the blank control group and lycopene treatment groups with different concentrations(0.5,1,2 μmol/L)were established.Finally,small molecular interference RNA(SiRNA)technique was used to further analyze the effect of PPAR y-LXR a signal pathway on lycopene regulating cholesterol absorption in Caco-2 cells.ResultsCaco-2 cells were incubated with different concentrations(0.5,1,2 μ mol/L)of lycopene for 24 hours,lycopene dose-dependently inhibited the cholesterol absorption(P<0.05,P<0.001,P<0.001)and the expression of NPC1L1 protein and mRNA(P<0.01,P<0.001,P<0.001)in Caco-2 cells,among which 2 μmol/L lycopene had the greatest inhibitory effect.In addition,lycopene treatment significantly increased the transcriptional activity of PPARy(P<0.05,P<0.05,P<0.01)and LXRa(P<0.05,P<0.01,P<0.001)and the expression of PPARγ(P<0.05,P<0.05,P<0.01)and LXRα(P<0.01,P<0.01,P<0.001).When PPARy-LXRa pathway was blocked,lycopene could no longer inhibit cholesterol absorption in Caco-2 cells.Conclusion1 Lycopene could inhibit cholesterol absorption by Caco-2 cells in a dose-dependent manner.2 Lycopene could decrease the protein and mRNA expression of Niemann-Peak Cl-like protein 1(NPC1L1),increase the mRNA expression of peroxisome proliferator activated receptor y(PPAR y)and liver X receptor α(LXR α),and inhibit cholesterol absorption in Caco-2 cells by regulating PPAR γ-LXR α-NPC1L1 signal pathway.3 This experiment further confirmed the inhibitory effect of lycopene on intestinal cholesterol absorption,which will provide a new scientific basis for the clinical application of lycopene in lowering cholesterol and preventing and treating diseases related to high cholesterol.