Downregulation of the low-density lipoprotein (LDL) receptor (LDLR) can lead to hypercholesterolemia and related conditions, including cardiovascular diseases. Statins are a class of LDL cholesterol-lowering agents and are best-selling medications for patients at high risk of developing cardiovascular diseases. Indeed, statins upregulate LDLR and proprotein convertase subtilisin/kexin type 9a (PCSK9), leading to LDLR lysosomal degradation, which interferes with the attenuation of hypercholesterolemia. In the present study, butein was found to decrease extracellular PCSK9 levels by reducing its mRNA expression, which was attributable to butein-mediated downregulation of HNF1α in HepG2 cells. Butein-mediated PCSK9 inhibition further reversed LDLR protein synthesis inhibition, which possibly occurred through butein-mediated inhibition of LDLR degradation. When treated as a combination of butein and a statin, butein reduced statin-mediated enhancement of PCSK9 protein expression. This resulted in a synergistic enhancement of LDLR protein expression, whereas butein alone marginally increased LDLR protein expression. These findings suggest that butein, a novel PCSK9 inhibitor, may be a potential alternative or adjunct to statin treatment.
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References
1.
SahebkarA, WattsGF: New LDL-cholesterol lowering therapies: Pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin Ther, 2013; 35:1082–1098.
2.
AlkhalilM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, reality or dream in managing patients with cardiovascular disease. Curr Drug Metab, 2019; 20:72–82.
3.
SeidahNG, BenjannetS, WickhamL, et al.: The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A, 2003; 100:928–933.
4.
AbifadelM, VarretM, RabesJP, et al.: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet, 2003; 34:154–156.
5.
RashidS, CurtisDE, GarutiR, et al.: Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci U S A, 2005; 102:5374–5379.
6.
CohenJC, BoerwinkleE, MosleyTHJr., HobbsHH: Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med, 2006; 354:1264–1272.
7.
MayneJ, DewpuraT, RaymondA, et al.: Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis, 2008; 7:22.
8.
NavareseEP, RaggiP: PCSK9 inhibition for patients with and without prior coronary revascularization: Potential additional benefit of a novel therapeutic agent. Atherosclerosis, 2018; 277:177–178.
9.
KimSW, ParkKG: Response: Serum Levels of PCSK9 Are Associated with Coronary Angiographic Severity in Patients with Acute Coronary Syndrome (Diabetes Metab J 2018;42:207–14). Diabetes Metab J, 2018; 42:350–352.
10.
SuiGG, XiaoHB, LuXY, SunZL: Naringin Activates AMPK Resulting in Altered Expression of SREBPs, PCSK9, and LDLR To Reduce Body Weight in Obese C57BL/6J Mice. J Agric Food Chem, 2018; 66:8983–8990.
11.
GaoWY, ChenPY, ChenSF, WuMJ, ChangHY, YenJH: Pinostrobin Inhibits Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) gene expression through the modulation of FoxO3a Protein in HepG2 Cells. J Agric Food Chem, 2018; 66:6083–6093.
12.
TaiMH, ChenPK, ChenPY, WuMJ, HoCT, YenJH: Curcumin enhances cell-surface LDLR level and promotes LDL uptake through downregulation of PCSK9 gene expression in HepG2 cells. Mol Nutr Food Res, 2014; 58:2133–2145.
13.
PelP, ChaeHS, NhoekP, YeoW, KimYM, ChinYW: Lignans from the fruits of Schisandra chinensis (Turcz.) Baill inhibit proprotein convertase subtilisin/kexin type 9 expression. Phytochemistry, 2017; 136:119–124.
14.
KitamuraK, OkadaY, OkadaK, KawaguchiY, NagaokaS: Epigallocatechin gallate induces an up-regulation of LDL receptor accompanied by a reduction of PCSK9 via the annexin A2-independent pathway in HepG2 cells. Mol Nutr Food Res, 2017; 61:1600836.
15.
SongKH, KimYH, ImAR, KimYH: Black Raspberry Extract Enhances LDL Uptake in HepG2 Cells by Suppressing PCSK9 Expression to Upregulate LDLR Expression. J Med Food, 2018; 21:560–567.
16.
ChoiHK, HwangJT, NamTG, et al.: Welsh onion extract inhibits PCSK9 expression contributing to the maintenance of the LDLR level under lipid depletion conditions of HepG2 cells. Food Funct, 2017; 8:4582–4591.
17.
HannahVC, OuJ, LuongA, GoldsteinJL, BrownMS: Unsaturated fatty acids down-regulate srebp isoforms 1a and 1c by two mechanisms in HEK-293 cells. J Biol Chem, 2001; 276:4365–4372.
18.
ParkHJ, LeeJY, ChungMY, et al.: Green tea extract suppresses NFkappaB activation and inflammatory responses in diet-induced obese rats with nonalcoholic steatohepatitis. J Nutr, 2012; 142:57–63.
19.
ZhangDW, LagaceTA, GarutiR, et al.: Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem, 2007; 282:18602–18612.
20.
PoirierS, MayerG, PouponV, et al.: Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: Evidence for an intracellular route. J Biol Chem, 2009; 284:28856–28864.
21.
JeongHJ, LeeHS, KimKS, KimYK, YoonD, ParkSW: Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res, 2008; 49:399–409.
22.
MendelDB, CrabtreeGR: HNF-1, a member of a novel class of dimerizing homeodomain proteins. J Biol Chem, 1991; 266:677–680.
23.
DongB, LiH, SinghAB, CaoA, LiuJ: Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1alpha protein expression through the ubiquitin-proteasome degradation pathway. J Biol Chem, 2015; 290:4047–4058.
24.
OchiaiA, MiyataS, IwaseM, ShimizuM, InoueJ, SatoR: Kaempferol stimulates gene expression of low-density lipoprotein receptor through activation of Sp1 in cultured hepatocytes. Sci Rep, 2016; 6:24940.
25.
MbikayM, MayneJ, ChretienM: Proprotein convertases subtilisin/kexin type 9, an enzyme turned escort protein: Hepatic and extra hepatic functions. J Diabetes, 2013; 5:391–405.
26.
LagaceTA, CurtisDE, GarutiR, et al.: Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest, 2006; 116:2995–3005.
27.
CameronJ, HollaOL, RanheimT, KulsethMA, BergeKE, LerenTP: Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum Mol Genet, 2006; 15:1551–1558.
