Xanthohumol Suppresses Mylip/Idol Gene Expression and Modulates LDLR Abundance and Activity in HepG2 Cells

Abstract

Xanthohumol, a prenylated flavonoid found in hops (Humulus lupulus L.), exhibits multiple biological activities such as antiatherosclerosis and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effects and molecular mechanisms of xanthohumol in hepatic cells. We found that xanthohumol (10 and 20 μM) increased the amount of cell-surface low-density lipoprotein receptor (LDLR) from 100.0 ± 2.1% to 115.0 ± 1.3% and 135.2 ± 2.7%, and enhanced the LDL uptake activity from 100.0 ± 0.9% to 139.1 ± 13.2% in HepG2 cells (p < 0.01). The mRNA levels of LDLR, HMGCR, and PCSK9 were not altered. Xanthohumol (20 μM) reduced the expression of inducible degrader of the LDL receptor (Mylip/Idol) mRNA and protein by approximately 45% (p < 0.01), which was reported to be associated with increases of LDLR level. We demonstrated that xanthohumol suppressed hepatic Mylip/Idol expression via counteracting liver X receptor (LXR) activation. The molecular docking results predicted that xanthohumol has a high binding affinity to interact with the LXRα ligand-binding domain, which may result in attenuation of LXRα-induced Mylip/Idol expression. Finally, we demonstrated that the Mylip/Idol expression and LDLR activity were synergistically changed by a combination of xanthohumol and simvastatin treatment. Our findings indicated that xanthohumol may regulate the LXR-Mylip/Idol axis to modulate hepatic LDLR abundance and activity.

Platycodin D enhances LDLR expression and LDL uptake via down-regulation of IDOL mRNA in hepatic cells

“…In this respect, several natural compounds have been tested for their synergistic effects with statins. The results showed that PCSK9 inhibitors such as curcumin, epigallocatechin gallate, and tanshinone IIA, and IDOL inhibitor such as xanthohumol enhanced the statin-mediated induction of LDLR mRNA and LDL-C uptake 16,[48][49][50] . In the present study, we demonstrated that co-treatment of HepG2 cells with PD and simvastatin resulted in further increase in LDLR expression and LDL-C uptake compared to simvastatin alone.…”

“…We also found that PD reduced the IDOL mRNA expression induced by synthetic LXR agonist T0901317, demonstrating that PD inhibits the LXR-dependent IDOL gene expression. The LXR-IDOL pathway can be inhibited by down-regulation of LXR expression 38,39 or competitively inhibiting LXR agonist binding into the ligand-binding pocket of LXR protein 16 . Our data showed that LXRα expression was not changed by PD, suggesting that PD may antagonize LXR transcriptional activity without affecting LXR expression.…”

Quantitative Analysis of Prenylated Constituents in Commercial Hops Samples Using Ultrahigh-Performance Supercritical Fluid Chromatography

“…▶ Table 3 Percentage of prenylated hops compounds (1)(2)(3)(4)(5) in investigated samples (Prod1-6) (n = 3) determined via quantitation using the PDA signal at 220 nm. The calculated recommended daily intake of reference substances in μg per dietary product (Prod1-4) is given in parentheses.…”

“…Apart from this, a considerable number of pharmacological research studies has been conducted on hop strobile and its constituents regarding estrogenic activities, anticancer properties, and anti-inflammatory effects [3][4][5]. Some of these results have been…”

IDOL gene variant is associated with hyperlipidemia in Han population in Xinjiang, China

“…Instantaneous adenoviral overexpression of mouse IDOL gene in wildtype model resulted in a significant decrease in LDLR protein and an increase in LDL-C levels 9 , 10 . Other possible downstream of IDOL includes VLDLR and ApoER2 11 . The upstream of IDOL is LXRs which have influence on extracellular cholesterol levels by combining with LXR element of IDOL 12 .…”