Roles of Spicy Foods and Their Bioactive Compounds in Management

Roles of Spicy Foods and Their Bioactive Compounds in Management. 1 of Hypercholesterolemia. 2. Yimin ZHAO, Zhen-Yu CHEN*. 3. Food & Nutritional ...
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Roles of Spicy Foods and Their Bioactive Compounds in Management of Hypercholesterolemia Yimin Zhao, and Zhen-Yu Chen J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b02975 • Publication Date (Web): 29 Jul 2018 Downloaded from http://pubs.acs.org on July 31, 2018

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Journal of Agricultural and Food Chemistry

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Roles of Spicy Foods and Their Bioactive Compounds in Management

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of Hypercholesterolemia

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Yimin ZHAO, Zhen-Yu CHEN*

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Food & Nutritional Sciences Programme, School of Life Sciences, The Chinese University of

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Hong Kong, Shatin, NT, Hong Kong, China

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Running title: Cholesterol-lowering Spice Foods

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*All correspondence should be addressed to Zhen-Yu Chen, School of Life Sciences, The

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Chinese University of Hong Kong, Shatin, NT, Hong Kong, Tel: (852) 3943-6382; email:

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[email protected]

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Abstract

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Hypercholesterolemia, as one of the major risk factors in development of cardiovascular

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diseases, is of mounting prevalence worldwide in recent years. Many nutraceuticals and

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phytochemical supplements serve as a promising complementary therapy in the management

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of hypercholesterolemia. Among them, spicy foods have attracted a special attention. Plasma

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lipid-lowering activity of garlic, ginger, and turmeric have been well studied in both humans and

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animals. Consumption of either 3 g/day of ginger or 2 g/day curcumin for over 4 weeks

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effectively reduced blood cholesterol in hypercholesterolemia subjects. However, effects of

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chili and black peppers on blood cholesterol are little studied clinically. The present review is to

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summarize the findings of recent studies on the efficacy and mechanism of spicy foods and

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their primary bioactive components in management of hypercholesterolemia from preclinical

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studies to clinical trials.

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Key words: spicy foods; pungent principle; hypercholesterolemia; cholesterol; cardiovascular

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diseases

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Introduction

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Hypercholesterolemia refers to a disorder in patients with elevation of plasma total

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cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), while reduction in plasma

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high-density lipoprotein cholesterol (HDL-C). Hypercholesterolemia is one of major risk factors

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in development of atherosclerosis and cardiovascular diseases. Emerging researches have

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shown that lipid-lowering nutraceuticals and phytochemicals, as a part of dietary supplements,

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are promising in attenuating hypercholesterolemia and preventing cardiovascular disease.1, 2

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Spices have a long history of culinary and medical use in the world. Common spicy foods

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include garlic, black pepper, and chili pepper. In recent years, consumption of spicy foods due

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to their health benefits has gained an increasing popularity. 3, 4 A large-scale cohort study in 0.5

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million people has shown that frequent consumption of spicy foods could significantly reduce

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deaths from ischemic heart disease by up to 22% after adjusting for confounding factors.5 A

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thorough review is in need to summarize recent findings concerning the efficacy and

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mechanisms of plasma cholesterol-lowering spicy foods. Therefore, the present review is to

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discuss how spice foods favorably regulate the cholesterol homeostasis and summarize the

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researches regarding plasma cholesterol-lowering potency of spicy foods from preclinical

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studies to clinical trials.

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Cholesterol Homeostasis

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Homeostasis of plasma cholesterol is a balance among its absorption in small intestine,

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metabolism in plasma, de novo synthesis, uptake, and bioconversion in the liver. Cholesterol

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absorption in small intestine is a very complex process. About 1200-1700 mg cholesterol enters

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the small intestinal lumen with 300-500 mg from diet and the remainder from bile fluid each

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day.6 Upon entering small intestine lumen, free cholesterol is taken up with an aid of Niemann-

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Pick C1 like 1 (NPC1L1) protein (Figure 1). When the absorbed free cholesterol reaches

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endoplasmic reticulum (ER), it esterifies or re-esterifies by acetyl-CoA acetyltransferase (ACAT2)

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to produce cholesteryl ester. Unlike NPC1L1, which recognizes both animal and plant sterols,

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ACAT2 preferentially esterifies cholesterol but not plant sterols.7 Next, cholesteryl ester is

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assembled into chylomicrons by microsomal triacylglycerol transport protein (MTP) followed by

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excretion into lymphatic system for body use.8 Un-esterified cholesterol is pumped out into the

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intestinal lumen by ATP-binding cassette sub-family G members 5 and 8 (ABCG5/8) for fecal

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excretion.9 In the colon, some unabsorbed cholesterol is metabolized by gut microbiota to

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produce other neutral sterols. It is therefore to use a sum of total fecal neutral sterols as a

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marker of cholesterol absorption.

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Liver is the central organ where cholesterol synthesis takes places and excessive

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cholesterol is catabolized and then eliminated via bile duct. Cholesterol metabolism in the liver

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is coordinately regulated by two transcriptional factors, namely, sterol regulatory element-

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binding protein 2 (SREBP2) and liver X receptor alpha (LXRα). The precursor of SREBP2, which

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binds to cholesterol-sensing SREBP cleavage-activating protein (SCAP), is anchored in the ER

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membrane and nuclear envelope (Figure 3).10 When the intracellular cholesterol drops,

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SREBP/SCAP disassociates with insulin-induced gene 1 protein (Insig-1) and migrates to the 4 ACS Paragon Plus Environment

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Golgi apparatus. The mature form of SREBP2 is then released, moves to nucleus, and activates

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the transcription of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA-R) and low-density

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lipoprotein receptor (LDLR) to maintain intercellular cholesterol balance.11 HMG-CoA-R is a

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rate-limiting enzyme for the de novo cholesterol synthesis and catalyzes the conversion of 3-

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hydroxy-3-methylglutaryl-CoA to mevalonate (Figure 2). Competitive inhibitors of HMG-CoA-R,

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such as statins, can repress de novo synthesis of cholesterol, and subsequently upregulate the

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expression of LDLR in the liver, leading to a decrease in plasma LDL-C concentrations.12 LDLR

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recognizes apolipoprotein B100 (ApoB100) and uptakes LDL-C from blood via endocytosis to

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maintain intercellular cholesterol balance.11 In addition to the transcriptional regulation of

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SREBP2, LDLR expression is also mediated by proprotein convertase subtilsin-kexin type 9

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(PCSK9). Recently, a PCSK9 inhibitor, Evolocumab, has been proven to be very effective in

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treating hypercholesterolemia.13

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LXRα and farnesoid X receptor (FXR) govern the removal of excessive cholesterol in the

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liver by converting cholesterol to bile acids. Cholesterol 7α-hydroxylase (CYP7A1) catalyzes the

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conversion of cholesterol to bile acids in the liver.14 Due to their detergent property, bile acids

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facilitate the digestion and absorption of dietary fat and fat-soluble nutrients like vitamin A.

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Primary bile acids, cholic and chenodeoxycholic acids, are produced in the liver, and conjugated

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with glycine or taurine before their excretion unto bile. Secondary bile acids, deoxycholic and

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lithocholic acids, are synthesized from primary bile acids in the intestine by gut microbiota.

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Most conjugated bile acids are reabsorbed through the enterohepatic circulation via the porta

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vein with less than 5% were excreted out into feces. In this connection, a sum of total fecal bile

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acids is a biomarker for conversion of cholesterol to its metabolites in the liver. 5 ACS Paragon Plus Environment

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Deregulation of cholesterol homeostasis can lead to elevation of plasma TC and LDL-C and

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reduction of plasma HDL-C. Hypercholesterolemia results in accumulation of excess cholesterol

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in the arterial wall, which leads to atherosclerosis. Apolipoprotein A-I (ApoA-I), synthesized in

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the liver and small intestine, takes up free cholesterol out of lipid-laden macrophages via ATP-

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binding cassette transporter member 1 (ABCA1) forming nascent HDL particles.15 Lecithin-

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cholesterol acyltransferase (LCAT) esterifies the free cholesterol in nascent HDL to produce

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mature HDL, which can further extract out free cholesterol from macrophages via ATP-binding

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cassette sub-family G member 1 (ABCG1).16 Subsequently, cholesteryl ester within mature HDL

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is absorbed by hepatic HDL receptor known as the scavenger receptor class B type 1 (SR-BI).

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Alternatively, the cholesteryl ester transfer protein (CETP) exchanges a cholesteryl ester in HDL

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particles with a triacylglycerol molecule from LDL and VLDL. The cholesteryl esters in LDL and

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VLDL are taken up by LDLR in the liver. In this regard, HDL-C is regarded as the good cholesterol,

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because it protects against atherogenesis.17

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Elevation of plasma triacylglycerol (TG) is an major cause of metabolic syndrome

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whereas there is no direct causal effect of TG on cardiovascular disease as that of cholesterol.1

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Hepatic de novo lipogenesis is activated at the transcriptional level by sterol regulatory

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element-binding protein 1c (SREBP1c) and carbohydrate-response element-binding protein

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(ChREBP) in an insulin-dependent and glucose-dependent manner, respectively.18 Once mature

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SREBP1c enter nucleus, it promotes the transcription of a series of lipogenic genes including

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fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), and acetyl CoA carboxylase (ACC).19

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ChREBP is activated by the metabolites from hepatic glycolysis and modulates the activities of 6 ACS Paragon Plus Environment

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FAS and ACC. Hepatic lipogenesis is inhibited by AMP-activated protein kinase (AMPK), which

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also controls the fatty acid β-oxidation together with peroxisome proliferator-activated

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receptor alpha (PPARα) in the liver.20

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Garlic

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Garlic (Allium sativum) has been used as a food condiment as well as an herb in

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traditional medicine across many cultures for thousands of years. It is estimated that

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commercial garlic supplement such as lyophilized garlic powder and aged garlic extract (AGE)

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remains one of the most popular dietary supplementation over the world nowadays.21 Garlic is

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the major dietary resource of organosulfur compounds among which γ-glutamylcysteines and

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alliin (Figure 4) are two most plentiful sulfur-containing constitutes in raw garlic bulbs.22 When

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garlic is processed, for example cut or crushed, alliinase is released and converts alliin to

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volatile allicin (Figure 4), which gives the unique pungent odor of garlic. Allicin is extremely

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unstable and quickly degrades into other organosulfur compounds like diallyl sulfide, diallyl

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disulfide, and diallyl trisulfide. The aging of garlic, via soaking sliced garlic in water or diluted

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ethanol at room temperature for several months, can lead to the formation of non-volatile

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odorless organosulfur compounds S-allyl-cysteine (SAC) and S-allyl-mercaptocysteine (SAMC,

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Figure 4), which substantially impart the health benefits of garlic.23 In addition, garlic also

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contains abundant saponins, vitamin A and C.24

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Numerous studies in vivo and in vitro have provided a strong evidence that garlic can favorably

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regulate the cholesterol homeostasis via various pathways (Table 1). It has been well

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established that garlic intake can decrease blood cholesterol by inhibiting hepatic de novo

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synthesis of cholesterol.1 Yeh et al. found that the water-extracts of garlic, mainly SAC, were

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less cytotoxic and much more effective in suppressing cholesterol synthesis in the liver than the

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lipid-extracts of garlic.25 Besides, SAC could repress plasma CETP activity and increase ABCA1

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expressions thus promoting reverse cholesterol efflux from macrophages (Figure 2).26, 27 A

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recent study showed that water-extracts of garlic may downregulate the gene expressions of

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multiple key transporters and enzymes involved in cholesterol absorption in the small intestine

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(Figure 1).28 Similarly, Lin et al. demonstrated that garlic administration led to decreased MTP

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gene expressions in the liver and small intestine thus impeding the assembly and secretion of

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chylomicrons from intestine to circulation.29 In addition, SAC was found to inhibit hepatic

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lipogenesis via increasing the phosphorylation of AMPK and ACC.30 Garlic-derived SAMC could

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also attenuate lipid accumulation in the liver via inhibiting apoptosis and enhancing

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autophagy.31 Moreover, treatment of vascular endothelial cells with AGE and SAC inhibited

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oxidized LDL-induced lipid peroxidation.32

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Clinical trials regarding the effect of garlic consumption on blood cholesterol levels have

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been frequently conducted in humans (Table 2). Although animal and cell culture studies have

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collectively proven that garlic is hypocholesterolemic, results from clinical investigations are

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inconsistent. Dozens of clinical trials have clearly demonstrated that garlic is capable of

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decreasing plasma cholesterol concentrations,33 while others have doubted the effectiveness of

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garlic in improving cholesterol homeostasis.34, 35 In a recent meta-analysis of 39 randomized 8 ACS Paragon Plus Environment

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controlled trials, Ried et al. found that administration of garlic supplements, regardless of the

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processing methods, significantly reduced blood TC and LDL-C by 15 mg/dL and 6 mg/dL,

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respectively.36 Interestingly, the subgroup analyses showed that the cholesterol-lowering

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effects of garlic were more remarkable in studies with a duration > 8 weeks and in

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hypercholesterolemic subjects whose baseline blood TC were higher than 200 mg/dL.36 Another

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meta-analysis also observed that garlic supplements could decrease blood TC and LDL-C to a

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greater extent in studies with longer duration and in subjects at a higher risk of cardiovascular

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disease.37 However, some clinical trials did not find any favorable effect of garlic on the blood

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levels of HDL-C or TG.35

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Ginger

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Ginger is the rhizome of Zingiber officinale and has long been used a spice as well as a

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medical plant in traditional Chinese medicine. Ginger is conventionally used as a folklore

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therapy for stomach ache and pregnancy-induced nausea due to its gastroprotective activity.

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The safety and effectiveness of ginger have been confirmed by a number of randomized

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controlled trials.38 Fresh ginger root contains about 5-8% oleoresin and up to 3% essential oil.39

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The pungency of ginger mainly comes from the presence of gingerols (Figure 5), among which

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6-gingerol is the most abundant accountable for about 25% of total oleoresins. When gingers

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are dried, gingerols are thermally labile and rapidly dehydrated to less pungent compounds

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called shogaols. Both gingerols and shogaols are considered as the active ingredients

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responsible for the physiological benefits of ginger.40, 41 After their absorption, gingerols and

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shogaols can be detected as their glucuronide and sulfate conjugates rather than their free

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forms in blood.42 The National Institutes of Health has recognized ginger, when used as a spice,

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is a generally safe food supplement with only minor side effects.43

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There are several mechanisms accounting for plasma cholesterol-lowering activity of

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ginger supplement (Table 1). It has been reported that the ethanol extracts of ginger can

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reduce blood cholesterol via inhibiting hepatic cholesterol biosynthesis while enhancing the

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uptake of cholesterol from circulation.44 Lei et al. showed that a gingerol- and shogaol-rich

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ginger extract was capable of reducing plasma TC and non-HDL-C via stimulating fecal

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excretions of neutral sterols and bile acids, accompanied by upregulation of hepatic CYP7A1

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and downregulation of intestinal NPC1L1, ACAT2, and MTP expressions in hamsters (Figure 1).45

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Besides, Oh et al. suggested that a gingerol-rich ginger extract could elevate blood HDL-C

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concentrations via modulating ABCA1, ApoA-I, and LCAT expressions in the liver and ameliorate

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the obese-associated mitochondrial dysfunction in high-fat diet-fed rats.46 A recent study has

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additionally demonstrated that 6-gingerol can improve hepatic cholesterol homeostasis via

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regulating LDLR and cholesterol efflux-related gene expressions in HepG2 cell line.47 Ginger

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supplementation can also dramatically lower the plasma ApoB concentration while it can raise

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ApoA-I, which serves as the main apolipoprotein of HDL particle.40 Besides, apart from gingerols

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and shogaols, ginger essential oils are also possible active ingredients because they are

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effective in decreasing blood TC and TG and avoid lipid over accumulation in the liver via

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inhibiting the activities of HMG-CoA-R, SREBP1c, and FAS in a murine model of nonalcoholic

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fatty liver disease.48

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The cholesterol-lowering property of ginger has been well confirmed in several clinical

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trials (Table 2). Three grams of ginger powder a day for 45 days led to a considerable reduction

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in blood TC, TG, and LDL-C in hyperlipidemic subjects.49 In the same way, Andallu et al.

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observed that daily intake of 3 g dried ginger powder for 30 days substantially decreased

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plasma TC, TG, LDL-C, and VLDL-C in patients with type 2 diabetes and hypercholesterolemia.50

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However, ginger administration only reduced blood TG while not affecting TC or LDL-C

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concentrations in diabetic or peritoneal dialysis patients.51, 52 The inconsistence may be partly

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due to a smaller dosage (1 g ginger powder per day) used in the latter two trials. Therefore, the

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dosage of ginger, processing methods, or healthy status of subjects might come into play and

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affect the hypocholesterolemic effectiveness of ginger.

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Turmeric

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Both turmeric (Curcuma longa) and ginger belong to the Zingiberaceae family, whereas

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Ginger has a blonde color while turmeric is orange or jacinth in appearance. Turmeric is

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extensively used as a spice and a natural pigment in textile and food industries in many Asian

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countries especially in India, the largest producer and consumer of turmeric in the world.53 The

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primary bioactive phytochemicals in turmeric are a group of curcuminoids namely curcumin,

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demethoxycurcumin, and bisdemethoxycurcumin (Figure 6), collectively accounting for about

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3-5% of fresh turmeric rhizome. These compounds give the orange color and have bitter

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flavor.54 Curcumin is the major curcuminoid in turmeric, and have been intensively investigated

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for its various physiological benefits including the anti-aging, anti-cancer, cardioprotective, and

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neuroprotective ativities.55 However, due to its instability under alkaline conditions, low water-

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solubility along with rapid metabolism and excretion, the oral bioavailability of curcumins is

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relatively low.56 A variety of approaches such as encapsulation with nanoparticles57 and

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liposomes58 have been employed to enhance the therapeutic efficacy of curcumin.

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A number of preclinical studies have systematically investigated the cholesterol-

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lowering activity of turmeric and its principle bioactive compound curcumin (Table 1). One

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important mechanism underlying the cholesterol-lowering activity of turmeric is that turmeric

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supplementation can help improve hepatic cholesterol homeostasis (Figure 2). Yiu et al.

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reported that a curcuminoid-rich extract of turmeric attenuated hypercholesterolemia via

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downregulating HMG-CoA-R gene expression, the rate-limiting enzyme in cholesterol de novo

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synthesis, while upregulating LDLR gene expression in rats.59 On the other hand, turmeric intake

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also led to higher fecal excretions of bile acids by activating CYP7A1 in rats, which catalyzes the

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conversion of cholesterol to bile acids, the major routine to eliminate excess cholesterol

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accumulation in the liver.60 Furthermore, curcumin administration enhances the fatty oxidation

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via upregulating AMPK and PPARα and inhibit lipogenesis via downregulating SREBP1c, ACC,

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and FAS in the liver.61 In addition, Feng et al. have demonstrated that curcumin can effectively

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inhibit the absorption of cholesterols in the small intestinal via downregulating the expression

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of SREBP2 and its downstream gene NPC1L1, which mediates the sterol transport across the

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enterocyte membrane, in high-cholesterol diet-fed hamsters (Figure 1).62 Curcumin has also

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been shown to promote the reverse cholesterol transportation by upregulating ABCA1

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expressions in macrophage-derived foam cells and ApoE-/- mice.63

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Although animal and cell culture studies have conclusively shown turmeric and curcumin

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possess a cholesterol-lowering activity, results from clinical trials are inconsistent (Table 2).

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Consumption of 2000 mg/day curcumin for 8 weeks could markedly reduce serum TC, LDL-C,

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and TG in patients with nonalcoholic fatty liver disease (NAFLD).64 In addition, Yang et al.

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observed that curcumin significantly reduced blood TG and LDL-C with elevation of HDL-C

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concentrations in subjects with metabolic syndrome who had received 1890 mg/day curcumin

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extract for 12 weeks.65 However, six-month administration of curcumin at 4 g/day did not

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exhibit any favorable effect on blood lipid parameters in elderly subjects with diagnosed

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cognitive dysfunction.66 Besides, a meta-analysis of 5 randomized controlled trials also did not

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support the conclusion that curcumin was hypocholesterolemic in spite of the highly

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heterogeneous populations.67 Perhaps, the inconsistent results might be related to the health

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status of subjects and the variability in absorption of curcumin among individuals.66 It is

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noteworthy that intervention of a combination of curcuminoids with piperine (100:1), a

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strategy to improve the oral bioavailability of curcuminoid68, at 1 g/day was found effective in

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ameliorating hypercholesterolemia.69

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Chili pepper

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Chili pepper is a general term referring to a series of species derived from cultivars of

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Capsicum genus such as bell pepper and cayenne pepper. Originated in Central America, chili

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pepper has a long history of culinary and medical use. Chili pepper is mainly cultivated and

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consumed in Mexico and Asian countries while much less popular in North America and

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Europe.70 It is estimated that the daily consumption of chili pepper can be up to 15 g per capita

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in Mexico and Korea.70 The pungent principles in chili pepper are a group of alkaloid

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compounds called capsaicinoids, mainly capsaicin and dihydrocapsaicin (Figure 7), which are

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responsible for the manifold physiological benefits associated with consumption of chili

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pepper.71 The content of capsaicinoids in chili peppers, ranging from about 90 to 3600 mg/kg,

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varies dramatically among different cultivars and different ripening stages.72, 73 Chili pepper and

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capsaicinoids are generally safe in humans even at ten times higher dosage of regular intake.74

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Although some observational studies have suggested that a high chili pepper intake might be a

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potential risk factor of gastric and gallbladder cancer, researchers have found in fact that such

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carcinogenic effects are more likely attributable to Aflatoxin contamination during the storage

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but not pepper itself.75-77

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Chili pepper and capsaicinoids have been found potential in preventing and treating

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hypercholesterolemia in cell cultures and animal models (Table 1). One mechanism underlying

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the cholesterol-lowering activity of capsaicinoids is that they can stimulate fecal excretion of

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bile acids. Capsaicinoids, when supplemented at a dosage mimicking its regular intake in

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humans, significantly reduced blood TC and LDL-C in hamsters and ovariectomized female rats

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via upregulating hepatic CYP7A1 gene expression (Figure 2).78, 79 Enhanced hepatic conversion

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of cholesterol to bile acids will cause cholesterol depletion in the liver, which subsequently

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leads to an increased cholesterol uptake from circulation by certain lipoprotein receptors to

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maintain cholesterol balance.80 Besides, Huang et al. reported that replacement of the nitrogen

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atom with oxygen atom in capsaicinoids (capsaicin and dihydrocapsaicin) led to the loss of their

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ameliorative effects on hypercholesterolemia in hamsters.81 Furthermore, supplementation of 14 ACS Paragon Plus Environment

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capsaicin lowered serum triacylglycerol concentration and stimulated lipid mobilization from

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adipose tissue but not affecting lipogenesis in obese rats.82 Acting as an agonist of transient

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receptor potential vanilloid type 1 (TRPV1), capsaicin can also prevented obese-related

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hyperlipidemia in mice.83

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However, randomized clinical trials regarding the effects of chili pepper and

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capsaicinoids on blood cholesterol are very limited (Table 2). The strong pungency of chili

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pepper and capsaicinoids may partly impede the implementation in clinical research as not all

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subjects can well tolerate it. Yuan et al. demonstrated that 4-week intervention of chili pepper

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at 1.25 g/day, equivalent to 5 mg/day capsaicin, successfully improved fasting blood lipid

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profiles compared with the placebo in women with gestational diabetes mellitus.84

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Consumption of chopped chili pepper at 30 g/day for 4 weeks also increased the resistance of

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serum LDL to oxidation in healthy subjects.85 Moreover, nonivamide, a less pungent structural

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analog of capsaicin, could inhibit fatty acid uptake and adipogenesis in differentiated Caco-286

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and in 3T3-L1 cells87, prevent weight gain without affecting blood TC, LDL-C, or TG in a 12-week

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intervention trial.88 Therefore, whether chili pepper and capsaicinoids possess a plasma

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cholesterol-lowering activity in humans warrants further investigations.

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Black pepper

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Black pepper (Piper nigrum) stems from India and is mainly cultivated in South Asia and

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Southeast Asia. The dried fruits of black pepper, also called peppercorn, is the most widely

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consumed spice in the world on a basis of the volume of international trade.89 In addition to 15 ACS Paragon Plus Environment

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food seasoning, black pepper has been used as food preservative, perfume ingredient, and folk

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medicine for treating gastrointestinal symptoms for centuries.90 Black pepper is rich in piperine,

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chavicine, essential oil, and vitamin A and K (Figure 7). Piperine, an alkaloid of weak pungency,

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makes up for about 2-9% of black pepper fruit, and is predominantly responsible for the health

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benefits associated with consumption of black pepper.89 Piperine is tasteless and much less

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spicy than capsaicin in chili pepper, whereby chavicine, the isomer of piperine, and volatile

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essential oil give the characteristic flavor and taste of black pepper on a larger scale.91 Eating

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black pepper is generally safe. A toxicological study demonstrated administration of black

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pepper and piperine at a dosage 20 times regular human intake did not cause any adverse

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effects in experimental rodents.92

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Plasma cholesterol-lowering properties of black pepper and piperine as well as

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associated molecular mechanisms have been studied in vivo and in vitro (Table 1). Piperine has

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been suggested to be effective in suppressing cholesterol absorption in the small intestine

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(Figure 2). It was observed that black pepper extract and piperine could dose-dependently

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repress intestinal cholesterol uptake via interfering the translocation of cholesterol transporter

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NPC1L1 proteins to the cytoplasm in Caco2 cell lines.93 Our research group has also found that

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piperine supplementation can considerably reduce plasma cholesterol and increase fecal

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output of cholesterol by downregulating small intestinal expressions of ACAT2 and MTP in

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hamsters (unpublished data). In addition, piperine is able to promote cholesterol efflux in THP-

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1-derived macrophages by inhibiting ABCA1 degradation (Figure 2).94 Another mechanism

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underlying the hypolipidemic activity of piperine is that it can modulate the activities of key

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enzymes involved in hepatic cholesterol homeostasis. Ochiai et al. showed that piperine could 16 ACS Paragon Plus Environment

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upregulate LDLR expression via stimulating the maturation of SREBP2 and facilitating its

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translocation from ER to Golgi thus increasing hepatic clearance of LDL-C from blood.95 As a

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LXRα antagonist, piperine could prevent and reverse a high-fat diet-induced obesity via

327

inhibiting hepatic lipogenesis and enhancing fatty acid oxidation in a AMPK-dependent manner

328

in mice.96,

329

cholesterol-lowering actions of black pepper and piperine, few clinical trials has investigated

330

the effects of black pepper and piperine on blood lipid profiles in humans.

97

Despite a large number of preclinical studies comprehensively outlined the

331

In summary, though the hypocholesterolemic effect of spicy foods is not always

332

reachable with doses usually employed for culinary purposes, plasma cholesterol-lowering spicy

333

foods along with their bioactive compounds are still potential in reducing the risk of

334

cardiovascular diseases. Nutraceuticals or dietary supplements derived from spicy foods are of

335

particular interest to both academia and industry. In this regard, more high-quality long-term

336

randomized clinical trials are in need to verify the effectiveness of spicy foods in management

337

of hypercholesterolemia. Future investigations shall also focus on the safety, bioavailability, and

338

pharmacokinetics of bioactive compounds of spicy foods.

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Bhat, B. G.; Chandrasekhara, N., Lack of adverse influence of black pepper, its oleoresin and piperine in the weanling rat. J Food Safety 1986, 7, 215-223.

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Butt, M. S.; Pasha, I.; Sultan, M. T.; Randhawa, M. A.; Saeed, F.; Ahmed, A., Black pepper and health claims: a comprehensive treatise. Crit Rev Food Sci Nutr 2013, 53, 875-886.

588 589

Meghwal, M.; Goswami, T. K., Piper nigrum and piperine: an update. Phytother Res 2013, 27, 1121-1130.

586 587

Srinivasan, K., Black pepper and its pungent principle-piperine: A review of diverse

93.

Duangjai, A.; Ingkaninan, K.; Praputbut, S.; Limpeanchob, N., Black pepper and piperine

592

reduce cholesterol uptake and enhance translocation of cholesterol transporter proteins.

593

J Nat Med 2013, 67, 303-310.

594 595

94.

Wang, L. M.; Palme, V.; Rotter, S.; Schilcher, N.; Cukaj, M.; Wang, D. D.; Ladurner, A.; Heiss, E. H.; Stangl, H.; Dirsch, V. M.; Atanasov, A. G., Piperine inhibits ABCA1 degradation

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and promotes cholesterol efflux from THP-1-derived macrophages. Mol Nutr Food Res

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2017, 61.

598

95.

Ochiai, A.; Miyata, S.; Shimizu, M.; Inoue, J.; Sato, R., Piperine induces hepatic low-density

599

lipoprotein receptor expression through proteolytic activation of sterol regulatory

600

element-binding proteins. Plos One 2015, 10.

601

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Jwa, H.; Choi, Y.; Park, U.-H.; Um, S.-J.; Yoon, S. K.; Park, T., Piperine, an LXRα antagonist,

602

protects against hepatic steatosis and improves insulin signaling in mice fed a high-fat diet.

603

Biochem Pharmacol 2012, 84, 1501-1510.

604 605

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Choi, S.; Choi, Y.; Choi, Y.; Kim, S.; Jang, J.; Park, T., Piperine reverses high fat diet-induced hepatic steatosis and insulin resistance in mice. Food Chem 2013, 141, 3627-3635.

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Figure Legends

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Figure 1. Effects of spicy foods on cholesterol absorption in the small intestine. The red bar-

609

headed line means inhibition or downregulation. NPC1L1, Niemann-Pick C1-Like 1 protein;

610

ACAT2, Acetyl-CoA acetyltransferase 2; MTP, microsomal triacylglycerol transport protein;

611

ABCG5/8, ATP-binding cassette sub-family G members 5 and 8.

612

Figure 2. Effects of spicy foods on cholesterol homeostasis in the liver and arterial wall

613

macrophages. The green arrow-headed line means activation or upregulation, while the red

614

bar-headed line means inhibition or downregulation. HMG-CoA-R, 3-hydroxy-3-methyl-glutaryl-

615

CoA reductase; CYP7A1, cholesterol 7α-hydroxylase; LDLR, low-density lipoprotein receptor; SR-

616

BI, scavenger receptor class B type 1; CETP, cholesteryl ester transfer protein; ApoA-I,

617

Apolipoprotein A-I; ABCG1, ATP-binding cassette sub-family G member 1; ABCA1, ATP-binding

618

cassette transporter member 1; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density

619

lipoprotein cholesterol.

620

Figure 3. Roles of SREPB2 in cholesterol homeostasis.

621

Figure 4. Major organosulfur compounds in garlic.

622

Figure 5. Chemical structures of gingerols and shogaols in ginger.

623

Figure 6. Chemical structures of major curcuminoids in turmeric.

624

Figure 7. Chemical structure of major bioactive compounds in chili pepper (capsaicin and

625

dihydrocapsaicin) and black pepper (piperine and chavincine).

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626 627

Figure 1. Effects of spicy foods on cholesterol absorption in the small intestine. The red bar-

628

headed line means inhibition or downregulation. NPC1L1, Niemann-Pick C1-Like 1 protein;

629

ACAT2, Acetyl-CoA acetyltransferase 2; MTP, microsomal triacylglycerol transport protein;

630

ABCG5/8, ATP-binding cassette sub-family G members 5 and 8.

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Figure 2. Effects of spicy foods on cholesterol homeostasis in the liver and arterial wall

633

macrophages. The green arrow-headed line means activation or upregulation, while the red

634

bar-headed line means inhibition or downregulation. HMG-CoA-R, 3-hydroxy-3-methyl-glutaryl-

635

CoA reductase; CYP7A1, cholesterol 7α-hydroxylase; LDLR, low-density lipoprotein receptor; SR-

636

BI, scavenger receptor class B type 1; CETP, cholesteryl ester transfer protein; ApoA-I,

637

Apolipoprotein A-I; ABCG1, ATP-binding cassette sub-family G member 1; ABCA1, ATP-binding

638

cassette transporter member 1; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density

639

lipoprotein cholesterol.

640

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Figure 3. Roles of SREPB2 in cholesterol homeostasis.

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Figure 4. Major organosulfur compounds in garlic.

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Figure 5. Chemical structures of gingerols and shogaols in ginger.

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Figure 6. Chemical structures of major curcuminoids in turmeric.

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Figure 7. Chemical structure of major bioactive compounds in chili pepper (capsaicin and

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dihydrocapsaicin) and black pepper (piperine and chavincine).

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Table 1. Summary of hypocholesterolemic spicy foods, their active ingredients and action targets in vivo and in vitro. Spicy food

Active ingredients

Targets

Ref

• Inhibition of HMG-CoA-R expression and activity in liver Garlic

S-allyl-cysteine & S-allylmercaptocysteine

• Inhibition of CETP activity in plasma • Upregulation of ABCA1 gene expression in macrophages

25-31

• Downregulation of MTP gene expression in small intestine • Upregulation of CYP7A1 & LDLR protein expressions in liver Ginger

Gingerols & shogaols

• Upregulation of ApoA-I & ABCA1 protein expressions in macrophages

44-48

• Downregulation of NPC1L1, ACAT2, & MTP gene expressions in small intestine • Downregulation of HMG-CoA-R gene expression in liver Turmeric

Curcuminoids: curcumin, demethoxycurcumin, & bisdemethoxycurcumin

• Activation of CYP7A1 & LDLR activities in liver • Upregulation of ABCA1 protein expression in macrophages

59-63

• Downregulation of NPC1L1 protein expression in small intestine

Chili pepper

Capsaicinoids: capsaicin & dihydrocapsaicin

• Upregulation of CYP7A1 protein expression in liver

78-83

• Upregulation of LDLR expression in liver Black pepper

Piperine & chavicine

• Downregulation of NPC1L1, ACAT2, & MTP protein expressions in small intestine • Inhibition of ABCA1 degradation in macrophages • Downregulation of LXRα protein expression in liver

656

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Table 2. Summary of plasma lipid-lowering activity of spicy foods in human studies. Spicy food

Study type umbrella review of meta-analyses

Garlic

meta-analysis meta-analysis meta-analysis clinical trial clinical trial

Ginger clinical trial clinical trial clinical trial clinical trial Turmeric

clinical trial

clinical trial meta-analysis

Observations • Eight of 9 meta-analyses reported garlic significantly reduced TC; • Garlic's effect on TC was significantly more pronounced in hypercholesterolemic subjects; • 6 of 7 meta-analyses showed garlic did not affect HDL-C; • 3 of 6 meta-analyses supported garlic is effective in reducing LDL-C while the remaining were not Garlic effectively reduced TC, LDL-C, & TG at 3 months but not at 6 months • Garlic supplementation for >2 months significantly reduced TC & LDL-C by 17 & 9 mg/dL, respectively, in subjects with hypercholesterolemia; • Garlic slightly raised HDL-C and did not affect TG Garlic significantly reduced TC & LDL-C by 16 & 8 mg/dL, respectively 3 g/day of ginger capsules for 45 days significantly reduced TC, TG, & LDL-C by 27, 36, & 17 mg/dL, respectively, in subjects with hyperlipidemia 3 g/day of ginger powder for 30 days significantly reduced TC, TG, & LDL-C by 8, 9, & 12 mg/dL, respectively, in subjects with hyperglycemia & hyperlipidemia 2 g/day of ginger for 2 months slightly reduced LDL-C & TG while not affecting TC or HDL-C in patients with type 2 diabetes 1 g/day of ginger for 10 weeks significantly reduced TG by 15% while not affecting TC, LDL-C or HDL-C in peritoneal dialysis patients 2000 mg/day of curcumin for 8 weeks significantly reduced TC, LDL-C, & TG by 20%, 23%, & 17%, respectively, in patients with nonalcoholic fatty liver disease 1890 mg/day of curcumin extract for 12 weeks significantly reduced TC, TG, & LDL-C by 10%, 29%, & 12%, respectively, in patients with metabolic syndrome • 4 g/day of curcumin for 6 months did not affect blood lipids in elderly patients with cognitive dysfunction; • The concentrations of plasma curcumin and serum cholesterol were positively and significantly correlated 1 g/day of curcumin: piperine mixture (100: 1) for 8 weeks significantly reduced TC, LDL-C, & TG by 10, 10, & 7 mg/dL, respectively, in patients with metabolic syndrome • Five clinical trials with heterogeneous populations were included; 39 ACS Paragon Plus Environment

Ref

33

34 36 37 49 50 51 52 64 65

66

69 67

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Chili pepper

clinical trial clinical trial

• Curcumin intake did not change blood lipids 1.25 g/day of chili pepper for 4 weeks significantly reduced TC & TG by 1.2 & 1.1 mmol/L, respectively, in pregnant women with gestational diabetes 30 g/day of chopped chili for 4 weeks inhibited LDL oxidation in healthy subjects

658

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TOC graphic

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Roles of Spicy Foods and Their Bioactive Compounds in Management of Hypercholesterolemia

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