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  • Introduction Piperine is a pungent alkaloid and accounts for


    Introduction Piperine is a pungent alkaloid and accounts for 2–5% dry weight in black and white peppers (Butt et al., 2013). Physiological benefits of piperine have been a subject of extensive research in recent years. Piperine is an antioxidant with strong anti-inflammatory and antiangiogenic activities (Doucette et al., 2013, Gupta et al., 2000, Tunsophon and Chootip, 2016). Piperine is capable of enhancing the D-Pantothenic acid of minerals and vitamins as well as polyphenols such as catechins and curcumin (Lambert et al., 2004, Shoba et al., 1998). It has been also reported that piperine can reduce blood lipids and attenuate hepatic steatosis in mice (Choi et al., 2013, Jwa et al., 2012). A recent large-scale prospective cohort study in 500,000 Chinese subjects has suggested that frequent consumption of spicy foods is associated with a reduced mortality of cardiovascular diseases by up to 22% after adjusting for the confounding factors (Lv et al., 2015). However, it remains unknown if piperine in spicy foods is the bioactive ingredient responsible for such observed cardiovascular benefits. It is poorly studied how dietary piperine may affect plasma cholesterol. Elevation of plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are associated with a high risk of heart disease, while elevation of high-density lipoprotein cholesterol (HDL-C) is associated with a low risk of cardiovascular disease. Plasma TC homeostasis is a function of absorption, synthesis, bioconversion, and excretion of cholesterol in the intestine and liver. Intestinal cholesterol absorption is a complex process which involves several transporters, enzymes and proteins including Niemann-Pick C1-like 1 protein (NPC1L1), acyl-CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP binding cassette transporter G (ABCG) (Chen, Jiao, & Ma, 2008). The removal of plasma cholesterol from circulation and the synthesis of cholesterol in the liver are mainly governed by sterol regulatory element binding protein 2 (SREBP2) and its downstream genes including low-density lipoprotein receptor (LDLR), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), while cholesterol elimination is mainly controlled by liver X receptor α (LXRα) and its downstream gene cholesterol 7α-hydroxylase (CYP7A1) (Chen et al., 2008). In this regard, Wang et al. (2017) have shown that piperine could inhibit the degradation of ATP-binding cassette transporter A1 (ABCA1) and increase the reverse cholesterol transportation in macrophages. However, it remains largely unknown how dietary piperine affects the cholesterol absorption in the intestine and cholesterol metabolism in the liver.
    Methods and materials
    Discussion The present study demonstrated that dietary piperine at 0.03% and 0.06% could effectively reduce plasma TC by 16–17% and non-HDL-C by 24–25%, respectively. This was in agreement with those reported in mice (Choi et al., 2013, Jwa et al., 2012) and rats (Tunsophon and Chootip, 2016, Vijayakumar and Nalini, 2006). The dosages of piperine used in the present study were equivalent to 200–400 mg/day and physiologically achievable for an adult (Reagan-Shaw et al., 2008). The present study was taken further to investigate the effect of dietary piperine on aortic atherosclerosis, finding it dose-dependently reduced the formation of fatty streak. If the frequent consumptions of spicy foods were associated with a reduced mortality from cardiovascular diseases, piperine would be most likely the active ingredient, which not only reduced plasma cholesterol concentration but also prevented the buildup of atherosclerotic plaque. The fecal sterol analysis clearly showed that dietary piperine significantly increased fecal excretion of cholesterol and total neutral sterols in a dose-dependent pattern (Table 4). In humans, 1200–1300 mg cholesterol enters the small intestine lumen with 300–400 mg coming from the diet and the rest from bile duct each day (Grundy, 1983). Most dietary and biliary cholesterol are absorbed in the small intestine and the remainder is excreted out into feces (Grundy, 1983) Most cholesterol, when passing through the large intestine, is utilized by gut microbiota and fermented into its derivatives namely, coprostanol, coprostanone, and dihydrocholesterol. In this regard, neutral sterols in feces should be summed as a biomarker of total cholesterol absorption and excretion (Zhang et al., 2017). In the present study, PL and PH diets remarkably increased fecal total neutral sterols by 84% and 109%, respectively (Table 4), suggesting that piperine reduced plasma TC via a mechanism of inhibiting cholesterol absorption and stimulating fecal output of neutral sterols.