Rui Jiao

Cholesterol-Lowering Nutraceuticals and Functional Foods

Epidemiological studies have demonstrated that elevated levels of plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are the major risk factors for coronary heart disease (CHD), whereas high concentrations of plasma high-density lipoprotein cholesterol (HDL-C) and a low ratio of TC to HDL-C are protective against CHD. A relationship between plasma TC and the risk of CHD is well established at concentrations above 240 mg/dL. In addition to the use of three main classes of cholesterol-lowering medications, including HMG-CoA reductase inhibitors, anion-exchange resins, and fibrates, a nutritionally balanced diet that reduces saturated fat and cholesterol intake has traditionally been the first goal of dietary therapy in lowering plasma TC. In recent years, nutraceuticals and functional foods have attracted much interest as possible alternative therapies for lowering plasma TC, especially for hypercholesterolemia patients, whose blood cholesterol level is marginally high (200-240 mg/dL) but not high enough to warrant the prescription of cholesterol-lowering medications. This review summarizes the findings of recent studies on the production, application, efficacy, and mechanisms of popular cholesterol-lowering nutraceuticals and functional foods.

Anti-hypertensive Nutraceuticals and Functional Foods

Epidemiological studies have demonstrated that elevated blood pressure is one of the major risk factors for stroke and coronary heart disease (CHD). A close association between blood pressure and the incidence of cardiovascular diseases is well established if systolic/diastolic blood pressure is above 140/90 mmHg. In recent years, nutraceuticals and functional foods have attracted considerable interest as potential alternative therapies for treatment of hypertension, especially for prehypertensive patients, whose blood pressure is marginally or mildly high but not high enough to warrant the prescription of blood pressure-lowering medications. This review summarizes the findings of recent studies on the chemistry, production, application, efficacy, and mechanisms of popular blood pressure-lowering nutraceuticals and functional foods including the Dietary Approaches to Stop Hypertension (DASH) diet plan, L-arginine, chlorogenic acid, fermented milk, garlic, onion, tea, soybean, ginger, hawthorn, and fish oil.

Choosing hamsters but not rats as a model for studying plasma cholesterol-lowering activity of functional foods.

Rats and hamsters are commonly used rodents to test the efficacy of cholesterol-lowering functional foods. In general, a diet containing 1% cholesterol for rats whereas a diet containing 0.1% cholesterol for hamsters is used to induce the hypercholesterolemia. The present study was carried out to compare hamsters with rats as a hypercholesterolemia model. Golden Syrian hamsters and Sprague Dawley rats were randomly divided into four groups and fed one of the four diets containing 0-0.9% cholesterol. Results demonstrated that serum total cholesterol (TC) in hamsters was raised 73-81% higher than that in rats fed the same cholesterol diets. Unlike rats in which HDL-C accounted very little for serum TC, the lipoprotein profile in hamsters was closer to that in humans. We investigated interaction of higher cholesterol diets with 3-hydroxy-3-methylglutary-CoA (HMG-CoA) reductase, low-density lipoprotein receptor (LDL-R) and cholesterol-7alpha-hydroxylase (CYP7A1), sterol regulatory element binding protein-2 (SREBP-2), and liver X receptor (LXR-alpha). Results showed hamsters and rats metabolized cholesterol differently. In view that hamsters synthesize and excrete cholesterol and bile acids in a manner similar to that in humans, it is concluded that hamsters but not rats shall be chosen as a model to study efficacy of cholesterol-lowering functional foods.

Biology of Ageing and Role of Dietary Antioxidants

Interest in relationship between diet and ageing is growing. Research has shown that dietary calorie restriction and some antioxidants extend lifespan in various ageing models. On the one hand, oxygen is essential to aerobic organisms because it is a final electron acceptor in mitochondria. On the other hand, oxygen is harmful because it can continuously generate reactive oxygen species (ROS), which are believed to be the factors causing ageing of an organism. To remove these ROS in cells, aerobic organisms possess an antioxidant defense system which consists of a series of enzymes, namely, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). In addition, dietary antioxidants including ascorbic acid, vitamin A, vitamin C, α-tocopherol, and plant flavonoids are also able to scavenge ROS in cells and therefore theoretically can extend the lifespan of organisms. In this connection, various antioxidants including tea catechins, theaflavins, apple polyphenols, black rice anthocyanins, and blueberry polyphenols have been shown to be capable of extending the lifespan of fruit flies. The purpose of this review is to brief the literature on modern biological theories of ageing and role of dietary antioxidants in ageing as well as underlying mechanisms by which antioxidants can prolong the lifespan with focus on fruit flies as an model.

Dietary calcium decreases plasma cholesterol by down-regulation of intestinal Niemann–Pick C1 like 1 and microsomal triacylglycerol transport protein and up-regulation of CYP7A1 and ABCG 5/8 in hamsters

SCOPE It has been shown that calcium supplementation favorably modifies plasma lipoprotein profile in postmenopausal women. The present study investigated the interaction of dietary calcium with genes of transporters, receptors and enzymes involved in cholesterol metabolism. METHODS AND RESULTS Forty-eight ovariectomized hamsters were fed one of the four diets containing 0, 2, 6 and 8 g calcium per kg. Plasma total cholesterol (TC), triacylglycerols (TG), and non-high density lipoprotein cholesterol were dose-dependently decreased, whereas high-density lipoprotein cholesterol (HDL-C) was dose-dependently increased with the increasing dietary calcium levels. Dietary calcium had no effect on protein mass of hepatic sterol regulatory element binding protein-2 (SREBP), liver X receptor-alpha (LXR), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), LDL receptor (LDLR) and cholesterol-7α-hydroxylase (CYP7A1). However, dietary calcium up-regulated the mRNA levels of hepatic CYP7A1 and intestinal ATP binding cassette transporters (ABCG5/8) whereas it down-regulated the intestinal Niemann-Pick C1 like 1 (NPC1L1) and microsomal triacylglycerol transport protein (MTP). In addition, dietary calcium increased the activity of intestinal acyl coenzyme A: cholesterol acyltransferase 2, while it decreased plasma cholesteryl ester transport protein (CETP). CONCLUSION Beneficial modification of lipoprotein profile by dietary calcium was mediated by sequestering bile acid absorption and enhancing excretion of fecal cholesterol, via up-regulation of mRNA CYP7A1 and intestinal ABCG 5/8 with down-regulation of mRNA NPC1L1 and MTP.

Hypocholesterolemic activity of grape seed proanthocyanidin is mediated by enhancement of bile acid excretion and up-regulation of CYP7A1

Interest in grape seed proanthocyanidin (GSP) as a cholesterol-lowering nutraceutical is growing. This study was to investigate the effect of GSP on blood cholesterol level and gene expression of cholesterol-regulating enzymes in Golden Syrian hamsters maintained on a 0.1% cholesterol diet. Results affirmed supplementation of 0.5% or 1.0% GSP could decrease plasma total cholesterol and triacylglycerol level. Western blot and real-time polymerase chain reaction analyses demonstrated GSP did not affect sterol regulatory element binding protein-2 and low-density lipoprotein receptor; however, it increased mRNA 3-hydroxy-3-methylglutaryl coenzyme A reductase. GSP had no effect on the protein mass of liver X receptor alpha (LXRα) but it decreased mRNA LXRα. Most importantly, GSP increased not only the protein level of cholesterol-7α-hydroxylase (CYP7A1) but also mRNA CYP7A1. It was concluded that the hypocholesterolemic activity of GSP was most likely mediated by enhancement of bile acid excretion and up-regulation of CYP7A1.

Cholesterol-lowering activity of sesamin is associated with down-regulation on genes of sterol transporters involved in cholesterol absorption.

Sesame seed is rich in sesamin. The present study was to (i) investigate the plasma cholesterol-lowering activity of dietary sesamin and (ii) examine the interaction of dietary sesamin with the gene expression of sterol transporters, enzymes, receptors, and proteins involved in cholesterol metabolism. Thirty hamsters were divided into three groups fed the control diet (CON) or one of two experimental diets containing 0.2% (SL) and 0.5% (SH) sesamin, respectively, for 6 weeks. Plasma total cholesterol (TC) levels in hamsters given the CON, SL, and SH diets were 6.62 ± 0.40, 5.32 ± 0.40, and 5.00 ± 0.44 mmol/L, respectively, indicating dietary sesamin could reduce plasma TC in a dose-dependent manner. Similarly, the excretion of total fecal neutral sterols was dose-dependently increased with the amounts of sesamin in diets (CON, 2.65 ± 0.57; SL, 4.30 ± 0.65; and SH, 5.84 ± 1.27 μmol/day). Addition of sesamin into diets was associated with down-regulation of mRNA of intestinal Niemann-Pick C1 like 1 protein (NPC1L1), acyl-CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP-binding cassette transporters subfamily G members 5 and 8 (ABCG5 and ABCG8). Results also showed that dietary sesamin could up-regulate hepatic cholesterol-7α-hydroxylase (CYP7A1), whereas it down-regulated hepatic 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase and liver X receptor alpha (LXRα). It was concluded that the cholesterol-lowering activity of sesamin was mediated by promoting the fecal excretion of sterols and modulating the genes involved in cholesterol absorption and metabolism.

Plasma Cholesterol-Lowering Activity of Gingerol- and Shogaol-Enriched Extract Is Mediated by Increasing Sterol Excretion

The present study investigated the cholesterol-lowering activity of gingerol- and shogaol-enriched ginger extract (GSE). Thirty hamsters were divided into three groups and fed the control diet or one of the two experimental diets containing 0.5 and 1.0% GSE. Plasma total cholesterol, liver cholesterol, and aorta atherosclerotic plaque were dose-dependently decreased with increasing amounts of GSE added into diets. The fecal sterol analysis showed dietary GSE increased the excretion of both neutral and acidic sterols in a dose-dependent manner. GSE down-regulated the mRNA levels of intestinal Niemann-Pick C1-like 1 protein (NPC1L1), acyl CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP binding cassette transporter 5 (ABCG5), whereas it up-regulated hepatic cholesterol-7α-hydroxylase (CYP7A1). It was concluded that beneficial modification of the lipoprotein profile by dietary GSE was mediated by enhancing excretion of fecal cholesterol and bile acids via up-regulation of hepatic CYP7A1 and down-regulation of mRNA of intestinal NPC1L1, ACAT2, and MTP.

Algal sterols are as effective as β-sitosterol in reducing plasma cholesterol concentration.

The present study examined the cholesterol-lowering activity of sterol extract (SE) derived from alga Schizochytrium sp. and its interaction with gene expression of transporters, receptors, and enzymes involved in cholesterol absorption and metabolism. GC-MS analyses found that SE was a mixture of various sterols including lathosterol, ergosterol, stigmasterol, 24-ethylcholesta-5,7,22-trienol, stigmasta-7,24(24(1))-dien-3β-ol, and cholesterol. Results showed that SE at doses of 0.06 and 0.30 g/kg diet were able to decrease plasma cholesterol concentration by 19.5 and 34%, respectively, compared with the control, in hamsters maintained on a 0.1% high-cholesterol diet. SE at a dose of 0.30 g/kg diet was as effective as β-sitosterol in reducing plasma total cholesterol (TC). SE-induced reduction in plasma TC was accompanied by down-regulation of intestinal acyl-CoA:cholesterol acyltransferase 2 (ACAT2) and hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and up-regulation of hepatic low-density lipoprotein (LDL) receptor. Addition of SE to the diet increased the excretion of total fecal sterols. It was concluded that SE possessed the same cholesterol-lowering activity as β-sitosterol and the underlying mechanisms were mediated by increasing sterol excretion and decreasing cholesterol absorption and synthesis.

Frequent cholesterol intake up-regulates intestinal NPC1L1, ACAT2, and MTP.

Dietary cholesterol elevates plasma total cholesterol (TC) level. However, no study to date has examined how cholesterol intake frequency interacts with the gene of sterol transporters, receptors, and enzymes involved in cholesterol metabolism. Thirty-three hamsters were divided into three groups with the control hamsters being given daily 9 mg of cholesterol in the diet (CD), whereas the second group being gavage-administered 3 mg of cholesterol three times per day (C-3) and the third group being gavage-administered 9 mg of cholesterol one time per day (C-1). The experiment lasted for 6 weeks. The hamsters were killed under carbon dioxide suffocation. Data demonstrated that plasma TC, non-high-density lipoprotein cholesterol, and triacylglycerols were elevated with the increasing cholesterol intake frequency. Western blotting analyses revealed that the intake frequency had no effect on protein mass of hepatic sterol regulatory element binding protein-2, liver X receptor-alpha, 3-hydroxy-3-methylglutaryl-CoA reductase, LDL receptor, and cholesterol-7alpha-hydroxylase. However, the frequent cholesterol intake down-regulated the mRNA level of hepatic LDL receptor. In contrast, the frequent cholesterol intake up-regulated the mRNA levels of intestinal Niemann-Pick C1-like 1 (NPC1L1), acyl coenzyme A:cholesterol acyltransferase 2 (ACAT2), and microsomal triacylglycerol transport protein (MTP). It was concluded that the cholesterol intake frequency-induced elevation in plasma TC was associated with greater cholesterol absorption, possibly mediated by up-regulation of NPC1L1, ACAT2, and MTP.