Evidence-Based Complementary and Alternative Medicine

Evidence-Based Complementary and Alternative Medicine / 2012 / Article
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The Potential Benefit of Complementary/Alternative Medicine in Cardiovascular Diseases

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Volume 2012 |Article ID 970635 | https://doi.org/10.1155/2012/970635

Wei-Jian Bei, Jiao Guo, Hai-Yun Wu, Yang Cao, "Lipid-Regulating Effect of Traditional Chinese Medicine: Mechanisms of Actions", Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 970635, 10 pages, 2012. https://doi.org/10.1155/2012/970635

Lipid-Regulating Effect of Traditional Chinese Medicine: Mechanisms of Actions

Academic Editor: Keji Chen
Received27 Oct 2011
Accepted08 Feb 2012
Published07 May 2012


Traditional Chinese medicine (TCM) has been increasingly used for the treatment of dyslipidemia and cardiovascular disease. Recently, much progress has been made in studies on the mechanisms of action of the lipid-regulating effect of TCM in animal experiments. Current researches showed that the lipid-regulating effect of TCM may be related to the following actions: (1) inhibiting intestinal absorption of lipids; (2) reducing the biosynthesis of endogenous lipids; (3) increasing the catabolism of lipid, sterol substances in live system; (4) increasing the secretion of sterol substances in live system; (5) regulating transcription factors related to lipid metabolism. This paper provides an overview of the recent advances and discusses their implications in future development of lipid-lowering drugs from TCM.

1. Introduction

Dyslipidemia refers to a disruption of lipid metabolism with exceeding serum levels of cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), and/or lower level of high-density lipoprotein-cholesterol (HDL-C). Serum levels of lipids and lipoprotein lipids are among the most potent and best substantiated risk factors for atherosclerotic diseases, particularly coronary heart disease (CHD) [1].

In human, lipids homeostasis is regulated by well-balanced mechanisms of intestinal uptake, endogenous synthesis and metabolism, transport in lipoprotein particles, and biliary excretion. The metabolism of cholesterol and fatty acids and their associated lipid transport particles (the lipoproteins) occurs in the gut, liver, and the peripheral tissues. Drugs that alter lipids concentration act mainly by altering the kinetics of one or more parts of the metabolic cycle.

Traditional Chinese medicine (TCM) has been increasingly used for the treatment of dyslipidemia and cardiovascular disease. In a previous paper, we have reviewed the efficacy of TCM for the treatment of dislipidemia, which has been confirmed by numerous clinical studies as well as laboratory researches [2].

In this paper, we will focus on the underlying mechanisms of actions of the lipid-regulation effect of TCM.

2. Inhibiting the Intestinal Absorption of Cholesterol

The absorption of dietary lipids (cholesterol, fatty acids, phospholipids, etc.) in the intestine is an important source of serum lipids. Cholesterol absorption is a key regulatory target in human lipid metabolism because it determines the amount of endogenous biliary as well as dietary cholesterol that is retained, thereby influencing cholesterol balance. Cholesterol in the intestinal tract is derived from the diet and bile. Whereas dietary intake ranges from <50 mg/day (pure vegetarians) to 750 mg/day, biliary cholesterol input is 3 to 10 times higher and ranges from 500 to 2,400 mg/day.

Plant sterols (e.g., stigmasterol and β-sitosterol) reduce serum LDL cholesterol level by competitively inhibiting intestinal cholesterol absorption. Recent findings also suggest that plant stanols/sterols actively influence cellular cholesterol metabolism within intestinal enterocytes, and, in response to the reduced supply of exogenous cholesterol, receptor-mediated lipoprotein cholesterol uptake is probably enhanced, as shown by increased LDL receptor expression [3].

Plant sterols are rich in a variety of traditional Chinese herbal medicine, such as fleece-flower root, cassia seed, eucommia, rhubarb, polygonum, and turmeric. In addition, cellulose, pectin, and agar, which are also rich in many Chinese herbal medicines, can reduce the absorption of cholesterol by forming a complex with cholate to impede the formation of cholesterol microparticles in the intestine [3, 4].

An in vivo experiment showed that the addition of 0.5% Fr2-3 (a tea leaf fraction containing 72% saponins with high in vitro antihypercholesterolemic activity) to a high-cholesterol diet suppressed the increase in serum cholesterol levels in rats. Fr2-3 induced a decrease in the liver cholesterol and triglyceride levels and an increase in the fecal excretion of cholesterol [4].

Anthraquinones in fleece-flower root inhibit absorption of cholesterol by increasing peristalsis in the intestine, enhance the converting of cholesterol into the bile acid, and therefore increase the cholesterol excretion via the bile [5]. Lecithin in fleece-flower root can also prevent the cholesterol deposition in the liver, increase the transportation and converting of cholesterol, thus reduce the concentration of cholesterol in serum and liver, and prevent its infiltrating into artery intima [5]. Furthermore, lecithin increases the activity of the cholesteryl esterase in vessel wall and inhibits the activity of Acyl coenzyme A-cholesterol acyltransferase (ACAT) [5]. Components in cassia proteins were reported to combine with bile acid and inhibit the absorption and aggradations of cholesterol in the body, leading to the decrease of serum level of TC, TG, and LDL in the hyperlipidemic rats [6].

Recent insights in the role of ATP-binding cassette (ABC) transporters ABCG5 and ABCG8, as well as the identification of Niemann-Pick C1 Like 1 (NPC1L1) protein as sterol transporter in the gut, focused attention on sterol transport processes in the small intestine and the liver [79]. NPC1L1 is the target of cholesterol absorption inhibitor Ezetimibe, which prevents NPC1L1 entering cells by avoiding NPC1L1 incorporated into vesicles, reducing the uptake of cholesterol by cells, impending the cholesterol absorption in intestine, and thus reducing the serum cholesterol concentrations significantly [10]. To date, no research has been reported on the effects of TCM on NPC1L1. We believe that screening TCM with suppressing activities on NPC1L1 will lead to the discovery of new components and new drugs for regulating cholesterol absorption in intestine and the new drugs of lipid lowering.

ACAT plays an important role in the absorption, transport, and storage of cholesterol by catalyzing the cholesterol and long-chain fatty acid to form cholesterol ester in vivo. Inhibition of ACAT may reduce the levels of plasma TC and LDL cholesterol, reduce the accumulation of cholesterol ester on the arterial wall, and prevent the formation of atherosclerosis. Hawthorn triterpene acids were reported to reduce blood TC by inhibiting the activation of ACAT in the hamster intestinal. Oleanolic acid (OA) and ursolic acid (UA) are responsible for the cholesterol-lowering effect of hawthorn by inhibiting intestinal ACAT activity. In addition, hawthorn and particularly its bioactive compounds (OA and UA) enhanced the cholesterol-lowering effect of plant sterols [11].

The microsomal triglyceride transfer protein (MTP) plays a pivotal role in the assembly and secretion of apolipoprotein B. Fresh garlic extract (FGE) at 3~6 g/L reduced MTP mRNA levels in both the human hepatoma HepG2 and intestinal carcinoma Caco-2 cells in dose-dependent fashion; maximal reductions reached to 72% and 59%, respectively. Rats fed FGE had significantly (46% of the control) lower intestinal MTP mRNA levels compared with the control rats. Long-term dietary supplementation of fresh garlic may exert a lipid-lowering effect partly through reducing intestinal MTP gene expression, thus suppressing the assembly and secretion of chylomicrons from intestine to the blood circulation [12].

3. Inhibiting the Endogenous Lipid Biosynthesis

Cells in vivo synthesize cholesterol via the mevalonate or HMG-CoA reductase (HMGCR) pathway. HMGCR and 7-dehydrocholesterol reductase (DHCR7) are the key rate-limiting enzymes of cholesterol synthesis and play vital roles in maintaining the cholesterol homeostasis. High-energy, high-fat, and high-saturated fatty acid diet, which can promote the synthesis of cholesterol, is the most common risk factor of hyperlipidemia, especially hypercholesterolemia.

Dozens of TCM herbs, including coptis (berberine), salvia, hawthorn, hawthorn-flavone, green tea and its active ingredient-catechol, triterpenoid in alisma, and gypenosides, have been reported to inhibit the endogenous synthesis of cholesterol [5].

Chang reported that berberine might inhibit the synthesis of cholesterol in the liver by upregulating the expression of hepatic Insig-2 gene at low dose, while at high dose, berberine reduces the expression of Insig-2 mRNA and protein [13].

Astragalus and Angelica were also reported to reduce the serum level of TC and LDL-C via inhibiting HMGCR activity in hyperlipidemic rat. Angelica and ferulic acid competed with 5-methyl acid pyrophosphate and inhibit the activity of methyl valerate-5-pyrophosphate decarboxylase of the rat liver cell and thereby inhibit the cholesterol biosynthesis [14].

High-dose aqueous extracts from artichoke leaves were found to inhibit cholesterol biosynthesis from 14C acetate in primary cultured rat hepatocytes in a concentration-dependent biphasic manner with moderate inhibition (approximately 20%). Cynaroside and particularly its aglycone luteolin in the artichoke extract were mainly responsible for inhibition of hepatic cholesterol biosynthesis in an indirect downmodulation of HMGCR, which may contribute to the recently confirmed hypolipidemic effect in human [15].

Fatty acid synthase (FAS) catalyzes the last step of fatty acid biosynthesis. Radix Notoginseng can inhibit FAS and thus lower serum TG level. Zhang reported that Panax notoginseng saponins [16] and green tea polyphenols [17, 18] have been reported to inhibit the mRNA and protein expression of Iκ-Bα and FAS in abdominal aortic tissue or in adipocyte, so as to lower lipid in high-fat hyperlipidemic rat.

4. Regulating Lipoprotein Lipase Activity

Lipoprotein lipase (LPL) and hepatic lipase (HL) play vital roles in the metabolism of chylomicrons and very low-density lipoprotein. Lacking of these two enzymes or their dynamic abnormalities might lead to dyslipidemia, metabolic syndrome, atherosclerosis, diabetes, preeclampsia, and other diseases [19, 20].

Increase in mRNA and protein levels of LPL might increase the activity of LPL in the adipose tissue and plasma, promote the clearance of VLDL and postprandial plasma lipid, reduce plasma triglycerides, increase HDL-C levels, and therefore prevent hypercholesterolemia induced by high fat diet and development of atherosclerosis [21, 22].

Berberine, hawthorn, turmeric, red yeast, rhubarb, and purslane might increase the expression and activity of the LPL [5, 2326]. Upregulating the transcription of LPL mRNA and LDL-R-mRNA in liver may also be one of the molecular mechanisms of blood lipids regulation of Xuezhikang, the red yeast extract [27]. Red ginseng acidic polysaccharide (RGAP), isolated from Korean red ginseng, was also reported to significantly enhance the serum activity of LPL [28].

Hepatic lipase (HL) is another important glycoprotein that catalyzes the hydrolysis of lipoprotein triacylglycerols and phospholipids. The majority of HL is synthesized and secreted by the liver and bound to heparin sulfate proteoglycans on the surface of sinusoidal endothelial cells and external surfaces of microvilli of parenchymal cells in the space of Disse, promoting the uptake of HDL and apolipoprotein-B-containing remnant particles [21, 29, 30]. Its catalytic activity contributes to the remodeling of LDL and high-density HDL to smaller, denser particles. HL also participates, with surface proteoglycans, the scavenger receptor B1 (SR-B1) and the LDL receptor-like protein, as a ligand in promoting hepatic uptake of lipoproteins. Recent in vivo and in vitro studies suggest alternative pathways, both through its catalytic activity and, independently, by which HL may modulate the development of cardiovascular and cerebrovascular disease [29, 30].

Saponins from Tribulus terrestris increase the activity and expression of HL in liver and the activity of LPL in skeletal muscle. These might be, at least in part, the underlying mechanisms for its effect in reducing serum levels of TG and TC [31].

Studies in our laboratory showed that Fufang Zhenzhu Tiaozhi Fang (FTZ) could improve serum lipid profile (TC, TG, apoB, LDL-C and HDL-C, apoA). Experimental studies in rat demonstrated that FTZ upregulates LPL and HL expression and increases the activity of both LPL and HL [32].

Pleurotus eryngii water extract (PEE) showed significant inhibitory activity against pancreatic lipase by preventing interactions between lipid emulsions and pancreatic lipase in vitro. The hypolipidemic effect of PEE in fat-loaded mice may be due to low absorption of fat caused by the inhibition of pancreatic lipase [33]. The ethyl acetate fraction of the rhizome of Alpinia officinarum (AO) exhibited potent inhibition of pancreatic lipase. 3-Methylethergalangin was isolated from the fraction as an inhibitor of pancreatic lipase with an IC50 value of 1.3 mg/mL (triolein as a substrate). AO and its ethyl acetate fraction significantly lowered the serum TG level in corn oil feeding-induced triglyceridemic mice, and serum TG and cholesterol in Triton WR-1339-induced hyperlipidemic mice. The hypolipidemic activity of AO and 3-methylethergalangin was due to the inhibition of pancreatic lipase [34].

The ethanolic extract of Ananas comosus L. leaves (AC) (0.40 g/kg) significantly reduced the increased serum triglycerides by 40% in fructose-fed mice. AC also significantly inhibited serum TC in Triton WR-1339 and alloxan plus high-fat diets-induced hyperlipidemic mice. AC (0.01–100 μg/mL) selectively activated LPL activity by 200%–400% and significantly inhibited HMGCR activity by 20%–49% in vitro. Furthermore, AC (0.40 g/kg) did no increase mice liver weights as fenofibrate (0.20 g/kg) administration. Xie et al. recognized that AC will be a new potential natural product for the treatment of hyperlipidemia through the mechanisms of inhibiting HMGCR and activating LPL activities, which was different from those with fibrates but may be partly similar to those with statins. It is hopeful that AC may serve as the adjuvant for fibrates [35].

5. Regulation of Cholesterol Transport

Inhibiting plasma cholesterol ester transfer protein (CETP) might increase the content of HDL-C and ApoA1, which is helpful to reduce TC, TG, and LDL-C. Lin et al. used a software to select CEPT inhibitor fictitiously. Dihydrotanshinone I, chosen as the target molecule with the CEPT-inhibiting active ingredient from salvia, was found to increase HDL and decrease LDL levels and could reduce TC and TG levels in serum and liver in the experimental hypercholesterolemic rat [39].

Berberine, an alkaloid isolated from the Chinese herb Coptis chinensis, has been recently identified as a new cholesterol-lowering drug and reduced serum TC and LDL-C levels in hyperlipidemia rats in a dose-dependent manner. The LDL cholesterol-lowering effect of berberine was attributed to its activity on hepatic LDLR expression via a new mechanism distinct from that of statins [3638]. In a human hepatoma cell line (HepG2) as well as in hyperlipidemic hamsters, Kong et al. showed that berberine upregulated the expression of LDLR through stabilization of its mRNA involving an extracellular-regulated-kinase- (ERK-)dependent mechanism [36].

Vijayakumar reported that hypolipidemic effect of a novel thermostable extract of Fenugreek seeds (Trigonella foenum-graecum, TEFS) was due to inhibition of fat accumulation and upregulation of LDLR. Under sterol-enriched condition, TEFS upregulated low-density lipoprotein receptor (LDLR) expression resulting in enhanced LDL uptake. TEFS administration for 15 days decreased the elevated serum TG, LDL-cholesterol, and body weight in a dose- and time-dependent manner in fat-supplement-fed C57BL6/J mice [42].

6. Promotion of Cholesterol Converting into Bile Acid and Excreting

Cholesterol is transformed into bile acids and excreted from the digestive tract under the catalysis of liver cholesterol 7α-hydroxylase (CYP7A1). About 2/5 synthesized cholesterol is converted into bile acids, under the catalysis of CYP7A1. Promoting CYP7A1 activity might enhance cholesterol to convert into bile acid, thereby to remove the cholesterol from the body, which is the primary mechanism for maintaining in cholesterol homeostasis [53, 54].

Xue et al. reported that radix Salviae miltiorrhizea extract containing danshensu is absorbed into blood after oral administration. Sodium danshensu (25~200 μg/mL) increased the percentage of cell viability in experiment of amphotericin B cell model and upregulated the expression of CYP7A mRNA in BRL cells, indicating that Danshensu can inhibit the synthesis of endogenous cholesterol and increase the expression of CYP7A1 mRNA to promote cholesterol transformation into bile acid in hamster liver cells [40, 41].

Zhang et al. reported that hawthorn fruit aqueous ethanolic extract decreased serum TC and TG by 10% and 13%, respectively, in hamsters which were fed with semisynthetic diet containing 0.1% cholesterol. Compared with the control, hawthorn fruit led to greater excretion of both neutral and acidic sterols. Further enzymatic assays showed that hawthorn fruit might promote the excretion of bile acids by upregulation of hepatic CYP7A1 activity and inhibition of cholesterol absorption mediated by downregulation of intestinal acyl CoA cholesterol acyltransferase (ACAT) activity [24].

Garcia-Diez reported that the addition of pectin to the diet resulted in lower serum and liver cholesterol concentrations (−27% and −17%, resp.) in male Wistar rats fed a fiber-free or a pectin-supplemented (7 g/100 g) diet for 4 wk. Fecal bile acid excretion (+168%) and the hepatic activity of CYP7A1 (+70%) were significantly higher in pectin-fed animals. HMGCR activity was also significantly greater (+11%) in the presence of dietary pectin. Pectin may increase hepatic synthesis of bile acids and liver depletion of cholesterol in rats, resulting in a higher rate of cholesterol synthesis and reduced serum cholesterol concentrations [46].

Vergara-Jimenez reported that plasma LDL cholesterol, TG, apolipoprotein B, and hepatic cholesteryl ester were lower in guinea pigs fed pectin (PE) and psyllium (PSY) compared to the control group. In addition, a 45% higher number of hepatic apoB/E receptors were observed by PE and PSY intake. Hepatic ACAT, HMGCR, and CYP7A1 activities were higher in the high-fat (HF) compared to the low-fat (LF) groups. PSY intake with HF resulted in upregulation of CYP7A1 and HMGCR activities. ApoB secretion was reduced by pectin and psyllium intake, while LDL fractional catabolic rates were 100% faster in guinea pigs fed PE or PSY in the HF groups [47].

Psyllium, the husks from Plantago ovata (PO), is recognized as a potent agent in lowering plasma cholesterol. Plasma triglycerides and LDL cholesterol were 34% and 23%, respectively, lower in the PO groups compared with the control male Hartley guinea pigs. Lecithin cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) activities were significantly affected by the PO diets. The control group had 100% and 36% higher LCAT and CETP activities, respectively, compared with the PO groups. Hepatic cholesteryl ester concentrations were 50% lower in the PO groups compared with the control. The activity of HMGCR was upregulated in the PO groups by 37%. Similarly, the activity of CYP7A1 was 33% higher in the PO groups. Fecal bile acids were 3 times higher in the PO groups than in the control group. PO exerts its hypolipidemic effect by affecting bile acid absorption and altering hepatic cholesterol metabolism [48].

FTZ significantly decreased the levels of serum TC, TG, and LDL-C whilst elevated the serum HDL-C and decreased serum atherogenic index (A.I.) values in high-lipid-diet-induced hyperlipidemic rats. Furthermore, FTZ showed significant antihyperlipidemic effect by at least three pathways in the high-lipid diet-induced-hyperlipidemic rats: (1) upregulating the gene expression and activity of CYP7A1 which promotes the conversion of cholesterol into bile acid; (2) downregulating the gene expression and activity of HMGCR to reduce de novo synthesis of cholesterol; (3) increasing the cholesterol excretion from feces. In these three pathways, HMGCR and CYP7A1 are two pivotal enzymes in lipid cholesterol metabolism and are expressed mainly in hepatic cells, which support the new TCM treatment strategy: modulating liver to treat hyperlipemia [49].

Metabolic enzymes and receptors involved in the lipid metabolism are subject to positive and negative regulation of dozens of transcription factors. At present, some of intensively investigated genes involved in the lipid metabolism are peroxisome proliferator-activated receptor (PPARs) [55, 56], sterol regulatory element binding protein (SREBPs) [57, 58, 60, 61], and liver receptor (the liver X receptors, LXR) [5961] gene. In recent years, there have been increasing studies to explore the regulating effects of TCM on transcription factors related to lipid metabolism.

7.1. PPARs Regulation

Studies have showed that several active ingredients from TCM herbs are PPARs agonists, and their active ingredient can activate PPARs.

Coptis and its active ingredient berberine could activate the PPARs, including PPARα [50] and PPAR-γ [23]. Hawthorn flavonoids might activate PPAR-α and increase the LPL activity of the blood and muscle tissue of hyperlipidemic rats or mice [24]. Curcumin could activate PPAR-γ and thus increase LPL activity in tissues and blood [25, 26].

Gynostemma pentaphyllum has showed antihyperlipidemic and hypoglycemic effects in the obese Zucker fatty diabetic rat model. Its active ingredient gypenoside XLIX was proved as a naturally occurring PPARα activator [43].

Gao et al. found that oleanolic acid extracted from Ligustrum lucidum could lower TC, TG, and LDL-C by activating the gene expression of cell PPAR-α, γ and protein kinase B [51]. Ginseng can also lower serum lipid by activating PPAR-α in cells [45].

7.2. SREBP Regulation

Lipid homeostasis is subject to the regulation of SREBPs, a class of membrane-bound transcription factor [57, 58, 60, 61].

Berberine promotes the translation of LDL-R gene by directly stabilizing the structure of SRE1 of LDL-R gene 5′ flanking region [36].

TEFS inhibited accumulation of fat in differentiating and differentiated 3T3-L1 cells via decreased expression of adipogenic factors such as PPAR-γ, SREBP-1, and CAAT element-binding proteins-alpha (c/EBP-alpha). TEFS treatment also significantly decreased cellular TG and cholesterol concentrations in HepG2 cells via reduced expression of SREBP-1, at mRNA as well as protein level [42].

Morroniside significantly decreased the elevated serum TG and alanine aminotransferase levels as well as hepatic glucose and lipids contents in a dose-dependent manner in type 2 diabetes model mice (C57BLKS/J db/db mice). The administration of morroniside also increased the antioxidative effects in the liver of db/db mice with hyperglycemia and dyslipidemia. The elevated expressions of nuclear factor-kappa Bp65, cyclooxygenase-2, inducible nitric oxide synthase, SREBP-1, and SREBP-2 were downregulated in the liver of db/db mice, but significantly increased PPARa expression by morroniside [52].

7.3. LXRs Regulation by TCM

LXRs are the receptors of nuclear-oxidized steroid. [5961]. LXRs were activated by inducing SREBP-1c and finally upregulated the genes involved in fatty acid and triglyceride synthetic genes and fatty acid synthase, such as FAS, SCD1. At the same time, LXRs were also involved in regulating insulin-induced SREBP-1c gene expression [62, 63].

The plant sterol guggulsterone [4, 17 (20)-pregnadiene-3,16-dione] (GS) is the active substance in guggulipid, the resin of the guggul tree (Commiphora mukul) used to treat a variety of disorders in humans, including dyslipidemia, obesity, and inflammation. GS is a highly efficacious antagonist of the farnesoid X receptor (FXR), a nuclear hormone receptor that is activated by bile acids. GS treatment decreases hepatic cholesterol in wild-type mice fed a high-cholesterol diet but is not effective in FXR-null mice. Inhibition of FXR activation is proposed as the basis for its cholesterol-lowering activity [44, 63].

Extraction of salvia (PSME, containing Danshensu, salvianolic acid A/B, and rosmarinic acid) might also regulate the expression of FXR/LXRα and then induce the expression of ATP-binding cassette transporter protein family (ABCB11) and mouse Mdr2 P-glycoprotein (also known as ABCB4), which is responsible for bile cholesterol solubility and bile secretion in bile salts and bile phospholipids. The transcriptional activation experiments showed that PSME is a coagonist for FXR and LXR α. PSME might improve lipid spectrum of male high-fat high-cholesterol diet-induced hyperlipidemic SD rats by activating FXR/LXR α, and PSME decreases liver and plasma TG through an FXR-SHP-SREBP-1c pathway [41].

8. Conclusion

In summary, TCM might regulate all processes of lipid metabolism (Figure 1). Targets related to the regulation of lipid metabolism by TCM herbs are mainly HMG-CoA reductase, FAS, LDL-R, CEPT, LPL, HL, CYP7A1, PPPA-α, SREBP, LXRa, and other targets (Tables 1, 2, Figure 1). The Chinese herb active components include alkaloids (berberine), phenols (Danshensu, Tea Polyphenols), flavonoids (curcumin and hawthorn flavonoids), triterpenoid saponins (ginseng saponins, glycosides from Tribulus terrestris), and statins (Monascus prime, red yeast), which demonstrates multitarget, multicomponent features of traditional Chinese herb medicine for the regulation of lipid metabolism (Tables 1 and 2, Figure 1).

Herb/ingredientsCh absorptionCh transport (LDLR, …)Lipid catabolism (HL, LPL)Ch synthesis (HMG-CoA R)BA synthesis (CYP7A1)OthersReference

Ananas comosus leavesLPL(+)() [35]
Astragalus, Angelica/ferulic acid()[5, 14]
Alpinia officinarum/3-MethylethergalanginPancreatic L()[34]
Artichoke/cynaroside, luteolin()[15]
Cassia protein()[6]
Coptis/berberine(+)LPL(+)()[32, 3638]
Danshen/dihydrotanshinone 1, salvianolic acid, danshensu(+)LDLR(+), CEPT()(−)(+)ABCA4/11(+)[3941]
FTZ(+)HL(+), LPL(+)()(+)[32]
Fenugreek (TEFS) (+)[42]
Fleece-flower root/anthraquinones, Lecithin, ()(+)(+)ACAT() [5]
Garlic MTP()[12]
Green tea/catechol, saponin()FAS()[17, 18]
Gynostemma pentaphyllum/gypenoside() [43]
Hawthorn/hawthorn-flavoneACAT()LPL(+)() (+)ACAT(−)[24]
Resin of the guggul tree/guggulsterone() (+)[44]
Hawthorn, ligustrum lucidum/oleanolic acid()ACAT()[11, 51]
Pleurotus eryngii()Pancreatic L()[33]
Plantago ovataCEPT()(+)(+)LACT()[48]
PsylliumCEPT(−)(+)(+)ApoB/LCAT() [47]
Red yeast/xuezhikang(+)LPL(+)()[27]
Tribulus terrestris/saponinsHL(+), LPL(+)[31]
Turmeric/curcuminLPL(+)[25, 26]


Berberineα(+), (+)SRE1Insig-i(+), CPTIA[23, 3638, 50]
Curcumin (+)[25, 26]
Danshen/dihydrotanshinone 1, salvianolic acid, and Danshensu rosmarinic acidα(+)(+)−1c()(+)ABCA1, ABCB4/11, SHP(+)[40, 41]
Gynostemma pentaphyllum/gypenosideα(+)[43]
Resin of the guggul tree/guggulsterone()AR/GR/MR(); PR/ERα(+)[44]
Ligustrum lucidum/oleanolic acidα(+), (+)protein kinase B (+)[51]
Hawthorn, hawthorn-flavoneα(+)[11, 24]
Morronisideα(+)−1();2() NF-kβ, iNOS, ()[52]
FTZα(+)() [49]
Fenugreek (TEFS) ()−1()cEBP-α()[42]

Notes for tables: (+): positive/upregulation; (−) negative/downregulation.

However, presently most of the studies on the mechanisms of TCM focus only on the efficacy of lipid lowering (serum lipid profile in TC, TG, LDL-C, and HDL-C) of a composite herb formula or its active ingredient and usually aim at one or two targets of lipid regulation. The interaction between the components in the composite acting on the same target is rarely involved, which failed to reflect the characteristics of the mechanism of Chinese herbal composite and the full-scale picture of Chinese medicine. It is needed to unveil the mystery of TCM and mine underground advantage of the TCM composites in dealing with the complex dyslipidemia by further study on the profound mechanism of TCM composite involving interaction among the multitargets and multicomponents.


ABC:ATP-binding cassette
ABCA1:ATP-binding cassette transporter A1
ABCB4:Mdr2 P-glycoprotein
ABCB11:ATP-binding cassette transporter protein family
ABCG5/8:ATP-binding cassette transporters ABCG5/ABCG8
AC:The ethanolic extract of Ananas comosus L. leaves
ACAT:Acyl coenzyme A cholesterol acyltransferase
ApoA/B:Apolipoprotein A/B
AR:Androgen receptors
BA:Bile acid
CETP:Cholesterol ester transfer protein
c/EBP-alpha:CAAT element-binding proteins-alpha
ERα:Estrogen receptor alpha
CYP7A1:Cholesterol 7α-hydroxylase
FAS:Fatty acid synthase
FTZ:Fufang Zhenzhu Tiao Zhi
FXR:Farnesoid X receptor
GR:Glucocorticoid receptors
HDL-C:High-density lipoprotein cholesterol
HL:Hepatic lipase
HMGCR:HMG-CoA reductase
iNOS:Inducible nitrogen oxide synthase
Insig-2:Insulin-induced gene-2
LACT:lecithin cholesterol acyltransferase
LDL-C:Low-density lipoprotein cholesterol
LDLR:LDL receptor
LPL:Lipoprotein lipase
LXRα:Liver X receptor α
MR:Mineralocorticoid receptors
MTP:Microsomal triglyceride transfer protein
NF-kβ:Nuclear factor-kappa beta
NPC1L1:Niemann-Pick C1 Like 1
PPARα/γ/δ:Peroxisome proliferators activated-receptor -alpha/gamma/delta
PR:Progesterone receptors
PSME:Salvia extract
SHP:Short heterodimer partner
SRE-1:Sterol regulatory element 1
SREBP-1/2:Sterol regulatory element-binding protein-1/2
SR-B1:Scavenger receptor B1
TCM:Traditional Chinese medicine
TEFS:Thermostable extract of fenugreek (Trigonella foenum-graecum) seeds
VLDL:Very low-density lipoprotein.


This paper is supported by National Science Foundation of China (Nos. 30973913, 81173626) and Guangdong Province and RP China Ministry of Education Projects of combining learning with research and industry (No. 2009B 090300349). The authors thank Dr. Lai-You Wang from the Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University for reviewing the paper.


  1. P. Durrington, “Dyslipidaemia,” The Lancet, vol. 362, no. 9385, pp. 717–731, 2003. View at: Publisher Site | Google Scholar
  2. H. Wu, J. Bei, and J. Guo, “Chinese herbal medicine for treatment of dislipidemia,” Journal of Geriatric Cardiology, vol. 6, no. 2, pp. 119–125, 2009. View at: Google Scholar
  3. X. G. Cao, G. Yu, X. L. Ye et al., “Study of the inhibition of cholesterol absorption by Chinese herbal extracts,” Chinese Traditional Patent Medicine, vol. 31, no. 4, pp. 616–618, 2009. View at: Google Scholar
  4. Y. Matsui, K. Kobayashi, H. Masuda et al., “Quantitative analysis of saponins in a tea-leaf extract and their antihypercholesterolemic activity,” Bioscience, Biotechnology and Biochemistry, vol. 73, no. 7, pp. 1513–1519, 2009. View at: Publisher Site | Google Scholar
  5. Y. J. Lin, J. H. Li, M. Yang et al., “Treating hyperlipidemia using traditional Chinese medicine,” World Science and Technology-Modernization of Traditional Chinese Medicine and Materia Medica, vol. 10, no. 1, pp. 103–106, 2008. View at: Google Scholar
  6. X.-E. Li and B.-J. Guo, “Effect of protein and anthraquinone glucosides from Cassia Seed on serum lipid of hyperlipidemia rats,” China Journal of Chinese Materia Medica, vol. 27, no. 5, pp. 375–376, 2002. View at: Google Scholar
  7. H. R. Davis, L. J. Zhu, L. M. Hoos et al., “Niemann-Pick C1 like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis,” Journal of Biological Chemistry, vol. 279, no. 32, pp. 33586–33592, 2004. View at: Publisher Site | Google Scholar
  8. W. Tang, Y. Ma, L. Jia et al., “Niemann-pick C1-like 1 is required for an liver X receptor agonist to raise plasma high density lipoprotein cholesterol in mice,” Arteriosclerosis Thrombusis Vascular Biology, vol. 28, no. 3, pp. 448–454, 2008. View at: Google Scholar
  9. H. Wittenburg and M. C. Carey, “Biliary cholesterol secretion by the twinned sterol half-transporters ABCG5 and ABCG8,” Journal of Clinical Investigation, vol. 110, no. 5, pp. 605–609, 2002. View at: Publisher Site | Google Scholar
  10. L. Ge, J. Wang, W. Qi et al., “The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1,” Cell Metabolism, vol. 7, no. 6, pp. 508–519, 2008. View at: Publisher Site | Google Scholar
  11. Y. Lin, M. A. Vermeer, and E. A. Trautwein, “Triterpenic acids present in hawthorn lower plasma cholesterol by inhibiting intestinal ACAT activity in hamsters,” Evidence-Based Complementary and Alternative Medicine, vol. 2011, Article ID 801272, 9 pages, 2011. View at: Publisher Site | Google Scholar
  12. M. C. Lin, E. J. Wang, C. Lee et al., “Garlic inhibits microsomal triglyceride transfer protein gene expression in human liver and intestinal cell lines and in rat intestine,” Journal of Nutrition, vol. 132, no. 6, pp. 1165–1168, 2002. View at: Google Scholar
  13. W. Chang, H. Wang, H. F. Yin, Q. X. Zhou, and J. X. Yang, “Effects of berberine on cholesterol metabolism and Insig-2 gene expression of hyperlipidemic rats,” Chinese Pharmacological Bulletin, vol. 25, no. 1, pp. 85–88, 2009. View at: Google Scholar
  14. J. Li, L. Yu, N. Li, and H. Wang, “Astragalus mongholicus and Angelica sinensis compound alleviates nephrotic hyperlipidemia in rats,” Chinese Medical Journal, vol. 113, no. 4, pp. 310–314, 2000. View at: Google Scholar
  15. R. Gebhardt, “Inhibition of cholesterol biosynthesis in primary cultured rat hepatocytes by artichoke (Cynara scolymus L.) extracts,” Journal of Pharmacology and Experimental Therapeutics, vol. 286, no. 3, pp. 1122–1128, 1998. View at: Google Scholar
  16. J. Yi, L. Xiaohui, L. Ya, and Z. Haigang, “Atherosclerosis lesion is accelerated by persistent systemic inflammation but attenuated by saponins from Panax Notoginseng in rabbits,” Journal of Medical Colleges of PLA, vol. 23, no. 1, pp. 38–44, 2008. View at: Publisher Site | Google Scholar
  17. W. P. Xiao, R. Zhang, and Y. H. Sun, “Enhancement of inhibitory activity of green tea extract on fatty acid synthase by hydrogen ion,” Chinese Journal of Biochemistry and Molecular Biology, vol. 22, no. 3, pp. 234–238, 2006. View at: Google Scholar
  18. X. Wang, K. S. Song, Q. X. Guo, and W. X. Tian, “The galloyl moiety of green tea catechins is the critical structural feature to inhibit fatty-acid synthase,” Biochemical Pharmacology, vol. 66, no. 10, pp. 2039–2047, 2003. View at: Publisher Site | Google Scholar
  19. J. R. Mead, S. A. Irvine, and D. P. Ramji, “Lipoprotein lipase: structure, function, regulation, and role in disease,” Journal of Molecular Medicine, vol. 80, no. 12, pp. 753–769, 2002. View at: Publisher Site | Google Scholar
  20. B. Perret, L. Mabile, L. Martinez, F. Tercé, R. Barbaras, and X. Collet, “Hepatic lipase: structure/function relationship, synthesis, and regulation,” Journal of Lipid Research, vol. 43, no. 8, pp. 1163–1169, 2002. View at: Google Scholar
  21. T. Nakamura and K. Kugiyama, “Triglycerides and remnant particles as risk factors for coronary artery disease,” Current Atherosclerosis Reports, vol. 8, no. 2, pp. 107–110, 2006. View at: Google Scholar
  22. N. Niho, M. Mutoh, M. Takahashi, K. Tsutsumi, T. Sugimura, and K. Wakabayashi, “Concurrent suppression of hyperlipidemia and intestinal polyp formation by NO-1886, increasing lipoprotein lipase activity in Min mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 8, pp. 2970–2974, 2005. View at: Publisher Site | Google Scholar
  23. Q. Y. Gao and S. M. Chen, “Effect of berberine on the expression of oxLDL, LPL in alveolar and peritoneal macrophages in diabetic rats,” Chinese Journal of Cardiovascular Medicine, vol. 13, pp. 277–279, 2008. View at: Google Scholar
  24. Z. Zhang, W. K. K. Ho, Y. Huang, and Z. Y. Chen, “Hypocholesterolemic activity of hawthorn fruit is mediated by regulation of cholesterol-7α-hydroxylase and acyl CoA: cholesterol acyltransferase,” Food Research International, vol. 35, no. 9, pp. 885–891, 2002. View at: Publisher Site | Google Scholar
  25. H. Manjunatha and K. Srinivasan, “Hypolipidemic and antioxidant effects of dietary curcumin and capsaicin in induced hypercholesterolemic rats,” Lipids, vol. 42, no. 12, pp. 1133–1142, 2007. View at: Publisher Site | Google Scholar
  26. E. M. Jang, M. S. Choi, U. J. Jung et al., “Beneficial effects of curcumin on hyperlipidemia and insulin resistance in high-fat-fed hamsters,” Metabolism, vol. 57, no. 11, pp. 1576–1583, 2008. View at: Publisher Site | Google Scholar
  27. P. E. McGovern, J. Zhang, J. Tang et al., “Fermented beverages of pre- and proto-historic China,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 51, pp. 17593–17598, 2004. View at: Publisher Site | Google Scholar
  28. Y. S. Kwak, J. S. Kyung, J. S. Kim, J. Y. Cho, and M. H. Rhee, “Anti-hyperlipidemic effects of red ginseng acidic polysaccharide from Korean red ginseng,” Biological and Pharmaceutical Bulletin, vol. 33, no. 3, pp. 468–472, 2010. View at: Publisher Site | Google Scholar
  29. A. Zambon, S. S. Deeb, P. Pauletto, G. Crepaldi, and J. D. Brunzell, “Hepatic lipase: a marker for cardiovascular disease risk and response to therapy,” Current Opinion in Lipidology, vol. 14, no. 2, pp. 179–189, 2003. View at: Publisher Site | Google Scholar
  30. H. Jansen, A. J. M. Verhoeven, and E. J. G. Sijbrands, “Hepatic lipase: a pro- or anti-atherogenic protein?” Journal of Lipid Research, vol. 43, no. 9, pp. 1352–1362, 2002. View at: Publisher Site | Google Scholar
  31. J. G. Li, W. J. Qu, S. Q. Wei et al., “Effect of tribu saponin from Tribulus terrestris on the lipoprotein lipase and (hepatic) lipase activity in lipid metabolic disorder mice,” Chinese Traditional Patent Medicine, vol. 29, no. 6, pp. 808–811, 2007. View at: Google Scholar
  32. J. Guo, W. J. Bei, C. P. Tang et al., “The effect of fufang zhenshu tiaozhi extract on hepatic lipase in diet-induced hyperlipidemic rats,” Zhong Yao Cai, vol. 32, pp. 582–585, 2009. View at: Google Scholar
  33. T. Mizutani, S. Inatomi, A. Inazu, and E. Kawahara, “Hypolipidemic effect of Pleurotus eryngii extract in fat-loaded mice,” Journal of Nutritional Science and Vitaminology, vol. 56, no. 1, pp. 48–53, 2010. View at: Google Scholar
  34. J. E. Shin, J. H. Myung, and D. H. Kim, “3-Methylethergalangin isolated from Alpinia officinarum inhibits pancreatic lipase,” Biological and Pharmaceutical Bulletin, vol. 26, no. 6, pp. 854–857, 2003. View at: Google Scholar
  35. W. Xie, W. Wang, H. Su, D. Xing, G. Cai, and L. Du, “Hypolipidemic mechanisms of Ananas comosus L. leaves in mice: different from fibrates but similar to statins,” Journal of Pharmacological Sciences, vol. 103, no. 3, pp. 267–274, 2007. View at: Publisher Site | Google Scholar
  36. W. Kong, J. Wei, P. Abidi et al., “Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins,” Nature Medicine, vol. 10, no. 12, pp. 1344–1351, 2004. View at: Publisher Site | Google Scholar
  37. W. N. Pan, S. K. Wang, and Z. Z. Wang, “Hydrochloric effect on Berberine effects on human liver cell line Bel-7402 expression of LDLR,” Journal of Nanjing Medical University, vol. 25, no. 12, p. 865, 2005. View at: Google Scholar
  38. P. Abidi, Y. Zhou, J. D. Jiang, and J. Liu, “Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 10, pp. 2170–2176, 2005. View at: Publisher Site | Google Scholar
  39. X. H. Lin, W. R. Xu, P. Liu et al., “The hyperlipidemic study of dihydrotanshinone I,” Zhong Cao Yao, vol. 39, pp. 1378–1380, 2008. View at: Google Scholar
  40. J. Xue, M. L. Xie, Z. L. Guo et al., “Effects of serum-drug of Radix Salviae Miltiorrhizae and Fructus Crataegi extracts on cholesterolmetabolism,” Zhong Cao Yao, vol. 38, no. 1, pp. 73–77, 2007. View at: Google Scholar
  41. W. Ji and B. Q. Gong, “Hypolipidemic activity and mechanism of purified herbal extract of Salvia miltiorrhiza in hyperlipidemic rats,” Journal of Ethnopharmacology, vol. 119, no. 2, pp. 291–298, 2008. View at: Publisher Site | Google Scholar
  42. M. V. Vijayakumar, V. Pandey, G. C. Mishra, and M. K. Bhat, “Hypolipidemic effect of fenugreek seeds is mediated through inhibition of fat accumulation and upregulation of LDL receptor,” Obesity, vol. 18, no. 4, pp. 667–674, 2010. View at: Publisher Site | Google Scholar
  43. T. H. W. Huang, V. H. Tran, B. D. Roufogalis, and Y. Li, “Gypenoside XLIX, a naturally occurring PPAR-α activator, inhibits cytokine-induced vascular cell adhesion molecule-1 expression and activity in human endothelial cells,” European Journal of Pharmacology, vol. 565, no. 1-3, pp. 158–165, 2007. View at: Publisher Site | Google Scholar
  44. T. P. Burris, C. Montrose, K. A. Houck et al., “The hypolipidemic natural product guggulsterone is a promiscuous steroid receptor ligand,” Molecular Pharmacology, vol. 67, no. 3, pp. 948–954, 2005. View at: Publisher Site | Google Scholar
  45. M. Yoon, H. Lee, S. Jeong et al., “Peroxisome proliferator-activated receptor is involved in the regulation of lipid metabolism by ginseng,” British Journal of Pharmacology, vol. 138, no. 7, pp. 1295–1302, 2003. View at: Publisher Site | Google Scholar
  46. F. Garcia-Diez, V. Garcia-Mediavilla, J. E. Bayon, and J. Gonzalez-Gallego, “Pectin feeding influences fecal bile acid excretion, hepatic bile acid and cholesterol synthesis and serum cholesterol in rats,” Journal of Nutrition, vol. 126, no. 7, pp. 1766–1771, 1996. View at: Google Scholar
  47. M. Vergara-Jimenez, K. Conde, S. K. Erickson, and M. L. Fernandez, “Hypolipidemic mechanisms of pectin and psyllium in guinea pigs fed high fat-sucrose diets: alterations on hepatic cholesterol metabolism,” Journal of Lipid Research, vol. 39, no. 7, pp. 1455–1465, 1998. View at: Google Scholar
  48. A. L. Romero, K. L. West, T. Zern, and M. L. Fernandez, “The seeds from Plantago ovata lower plasma lipids by altering hepatic and bile acid metabolism in guinea pigs,” Journal of Nutrition, vol. 132, no. 6, pp. 1194–1198, 2002. View at: Google Scholar
  49. J. Guo, W. Bei, Y. Hu et al., “A new TCM formula FTZ lowers serum cholesterol by regulating HMG-CoA reductase and CYP7A1 in hyperlipidemic rats,” Journal of Ethnopharmacology, vol. 135, no. 2, pp. 299–307, 2011. View at: Publisher Site | Google Scholar
  50. L. Y. Shi, M. Tian, W. Chang, Y. Yuan, and Q. X. Zhou, “Effect of Berberine on the expression of lipid metabolism-associated gene PPARα and CPTIA,” Chinese Pharmacological Bulletin, vol. 24, no. 11, pp. 1461–1464, 2008. View at: Google Scholar
  51. D. Gao, Q. Li, Y. Li et al., “Antidiabetic potential of oleanolic acid from Ligustrum lucidum Ait,” Canadian Journal of Physiology and Pharmacology, vol. 85, no. 11, pp. 1076–1083, 2007. View at: Publisher Site | Google Scholar
  52. C. H. Park, N. Yamabe, J. S. Noh, K. S. Kang, T. Tanaka, and T. Yokozawa, “The beneficial effects of morroniside on the inflammatory response and lipid metabolism in the liver of db/db mice,” Biological and Pharmaceutical Bulletin, vol. 32, no. 10, pp. 1734–1740, 2009. View at: Publisher Site | Google Scholar
  53. A. Chawla, E. Saez, and R. M. Evans, “Don't know much bile-ology,” Cell, vol. 103, no. 1, pp. 1–4, 2000. View at: Google Scholar
  54. J. Y. L. Chiang, “Bile acids: regulation of synthesis,” Journal of Lipid Research, vol. 50, no. 10, pp. 1955–1966, 2009. View at: Publisher Site | Google Scholar
  55. J. Berger and D. E. Moller, “The mechanisms of action of PPARs,” Annual Review of Medicine, vol. 53, pp. 409–435, 2002. View at: Publisher Site | Google Scholar
  56. B. Staels and J. C. Fruchart, “Therapeutic roles of peroxisome proliferator-activated receptor agonists,” Diabetes, vol. 54, no. 8, pp. 2460–2470, 2005. View at: Publisher Site | Google Scholar
  57. M. S. Brown and J. L. Goldstein, “The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor,” Cell, vol. 89, no. 3, pp. 331–340, 1997. View at: Publisher Site | Google Scholar
  58. J. D. Horton, J. L. Goldstein, and M. S. Brown, “SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver,” Journal of Clinical Investigation, vol. 109, no. 9, pp. 1125–1131, 2002. View at: Publisher Site | Google Scholar
  59. P. A. Edwards, H. R. Kast, and A. M. Anisfeld, “BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis,” Journal of Lipid Research, vol. 43, no. 1, pp. 2–12, 2002. View at: Google Scholar
  60. R. Raghow, C. Yellaturu, X. Deng, E. A. Park, and M. B. Elam, “SREBPs: the crossroads of physiological and pathological lipid homeostasis,” Trends in Endocrinology and Metabolism, vol. 19, no. 2, pp. 65–73, 2008. View at: Publisher Site | Google Scholar
  61. J. J. Repa, G. Liang, J. Ou et al., “Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ,” Genes and Development, vol. 14, no. 22, pp. 2819–2830, 2000. View at: Publisher Site | Google Scholar
  62. S. B. Joseph, B. A. Laffitte, P. H. Patel et al., “Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors,” Journal of Biological Chemistry, vol. 277, no. 13, pp. 11019–11025, 2002. View at: Publisher Site | Google Scholar
  63. N. L. Urizar, A. B. Liverman, D. T. Dodds et al., “A natural product that lowers cholesterol as an antagonist ligand for FXR,” Science, vol. 296, no. 5573, pp. 1703–1706, 2002. View at: Publisher Site | Google Scholar

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