The present study is the first
The present study is the first time to investigate the effect of piperine on intestinal sterol transporters and enzymes in the small intestine. NPC1L1 is a sterol transporter responsible for taking up cholesterol from the lumen to enterocytes (Davis et al., 2004). ACAT2 is an enzyme, which esterifies cholesterol to cholesteryl ester (CE) in enterocytes. Subsequently, MTP assembles CE with apolipoprotein B into chylomicrons before entering the lymphatic system (Jamil et al., 1995). Results clearly showed piperine supplementation was associated with down-regulation on the mRNA of intestinal NPC1L1, ACAT2, and MTP in a dose-dependent manner and protein mass of of ACAT2 and MTP (Fig. 3). In fact, piperine has been shown to reduce the cholesterol uptake and inhibit the gene expression of NPC1L1 in Caco-2 monolayer (Duangjai, Ingkaninan, Praputbut, & Limpeanchob, 2013). It was therefore concluded that plasma cholesterol-lowering activity of piperine was mediated by inhibition on cholesterol perifosine via down-regulation of NPC1L1, ACAT2 and MTP.
Excess cholesterol in the liver is eliminated via the conversion of cholesterol to bile acids (Chen et al., 2008). In the present study, we found that piperine supplementation only caused a slight increase in the fecal exertion of total bile acids. In the liver, CYP7A1 is an enzyme, which catalyzes the synthesis of bile acids, while LXRα mediates the stimulation of gene expression of CYP7A1. Dietary piperine administration did not significantly alter the mRNA and protein abundances of LXRα and CYP7A1, suggesting that plasma cholesterol-lowering activity of piperine was unlikely mediated via enhancing the synthesis or elimination of bile acids. HMGCR is an enzyme regulating cholesterol synthesis, while LDLR mediates the cholesterol removal from circulation. SREBP2 regulates the transcription of HGGCR and LDLR. Results from RT-PCR and Western Blot analyses did not find dietary piperine had any significant effect on SREBP2, HMGCR and LDLR, indicating that plasma cholesterol-lowering activity was unlikely mediated by inhibition on hepatic cholesterol synthesis or removal.
Spicy foods emerge as promising nutraceutical therapies for treating hyperchloremia in recent years (Zhao & Chen, 2018). Although black pepper is the most widely consumed spicy food, clinical trials regarding its effects on blood cholesterol are still lacking (Zhao & Chen, 2018). Therefore, the present study serves as in vivo evidence to demonstrate that piperine possesses a plasma cholesterol-lowering activity, which should be tested in human trials in the future.
Conflict of interest
Animal experiment ethical file
Acknowledgement This project was partially supported by a grant from the Health and Medical Research Fund, The Food and Health Bureau, The Government of the Hong Kong Special Administrative Region, China (Project No. 13140111).
Introduction Atherosclerosis is the major cause of coronary heart disease caused by dysfunction in lipoprotein cholesterol metabolism . Excessive absorption of dietary and biliary cholesterol into the intestine and dysregulation in cholesterol homeostasis result in elevated plasma cholesterol levels, which may promote the development of atherosclerosis . Several animal studies have demonstrated that a reduction in intestinal cholesterol absorption exerts strong cholesterol-lowering and atheroprotective effects , . Cholesterol absorption in the small intestine has been recently identified to be mediated by Niemann-Pick C1-like 1 (NPC1L1) protein, a key transporter for intestinal cholesterol absorption . NPC1L1 is highly expressed in the mucosa of the small intestine and is required for cholesterol absorption . Deficiency or inhibition of NPC1L1 in mice causes a marked reduction in cholesterol absorption  and is completely resistant to diet-induced hypercholesterolemia ,  and atherosclerosis caused by apolipoprotein E (ApoE) deficiency , .