Inhibitory Effect of KIOM-2015EW, a Water Extract of Acer Palmatum Thumb, on PCSK9 Expression in a Fructose-Induced in Vitro Fatty Liver Model

Abstract

Background: Acer Palmatum Thumb is a traditional medicinal herb used in East Asia, and previous studies performed by our team revealed the anti-inflammatory and neuroprotective effects of KIOM-2015EW, a water extract of Acer Palmatum Thumb leaves. Hence, this study aimed to explore the inhibitory effects of KIOM-2015EW on decreasing proprotein convertase subtilisin/kexin type 9 (PCSK9) expression in a fructose-induced fatty liver model. Method: HepG2, a human hepatocyte-derived hepatocellular carcinoma, was exposed to low-glucose Dulbeccos modified Eagles medium (DMEM) media with or without fructose, statins, and KIOM-2015EW. Cell viability was measured by cell counting kit-8 (CCK-8) analysis, and fat accumulation and low-density lipoprotein (LDL) uptake were, respectively, detected by oil-red O staining and LDL-uptake assay. The mRNA and protein levels of PCSK9, low-density lipoprotein receptor (LDLR), peroxisome proliferator-activated receptor alpha (PPARα), and retinoid X receptor alpha (RXRα) were measured via real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. PCSK9 transcription factors were predicted via chemical-protein interactions using the Stichi database. Result: KIOM-2015EW significantly decreased fat accumulation and recovered LDL uptake in fructose-induced cells (p < 0.05). That also decreased PCSK9 levels induced by fructose or fructose/lovastatin (p < 0.05) and recovered LDLR mRNA expression. Chemical-protein interactions showed that eleven transcription factors (TFs) interacted with two major compounds of KIOM-2015EW. Inhibition of PPARα/RXRα and mitogen-activated protein kinase (p38) significantly attenuated PCSK9 expression induced by fructose. KIOM-2015EW decreased PPARα and RXRα expression which was increased by fructose and fructose/statin (p < 0.05). Conclusion: This study suggested that KIOM-2015EW may lower serum cholesterol, and it can be used as a natural substance for the prevention or treatment of hypercholesterolemia.