Antioxidant and hypolipidaemic properties of red seaweed,Gracilaria changii

The edible red seaweed, Gracilaria changii, was collected from the coastal area of Sarawak, Malaysia, and evaluated for its hypolipidaemic properties using high cholesterol/high fat (HF) induced male Sprague–Dawley rats. In the in vivo study, the HF diet group showed significantly higher total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), atherogenic index (AI) and body weight gain as compared to other treatment groups. At the end of treatment period, rats fed with a HF diet supplemented with 5 % freeze-dried G. changii powder had significantly reduced plasma TC (?39.19 %), LDL-C (?36.36 %), and triglycerides (TG) content (? 25.45 %). Meanwhile, 10 % seaweed powder significantly lowered the plasma TC, LDL-C and TG content by ?40.34, ?35.95 and ?30.91 % respectively, compared to the HF group. The AI of rats supplemented with 10 % seaweed powder was the lowest among the treatment groups and indicates a lowered risk for cardiovascular diseases. The plasma lipid peroxidation of the seaweed powder-fed groups was also significantly lower than the HF group, while the erythrocyte enzyme antioxidant activities of superoxide dismutase, catalase and glutathione peroxidase of the treatment groups were also improved. Diets supplemented with seaweed powder also decreased plasma aspartate aminotransferase and the alanine aminotransferase levels.     

Medium-Chain Fatty Acids Enhanced the Excretion of Fecal Cholesterol and Cholic Acid in C57BL/6J Mice Fed a Cholesterol-Rich Diet

The objective of the present study was to investigate the cholesterol-reducing effect of medium-chain fatty acids (MCFAs) completed by elevated excretion of fecal neutral steroids and/or bile acids. Blood and liver lipid profiles, fecal neutral steroids, bile acids, and mRNA and protein expression of the genes relevant to cholesterol homeostasis were measured and analyzed in C57BL/6J mice fed a cholesterol-rich diet with 2% caprylic acid or capric acid for 12 weeks. Blood total cholesterol and low-density lipoprotein cholesterol (LDL-c) levels were reduced significantly as compared to diet with palmitic acid or stearic acid. Caprylic acid promoted the excretion of fecal neutral steroids, especially cholesterol. The excretion of fecal bile acids, mainly in the form of cholic acid was enhanced and accompanied by elevated expression of mRNA and the protein of hepatic cholesterol 7α-hydroxylase (CYP7A1). These results indicate that MCFAs can reduce blood cholesterol by promoting the excretion of fecal cholesterol and cholic acid.     

Comparative regulation of major enzymes in the bile acid biosynthesis pathway by cholesterol, cholate and taurine in mice and rats

These enzymes play important roles in the biosynthesis of bile acids. They are cholesterol 7alpha-hydroxylase (CYP7A1), the rate limiting enzyme in the classic pathway, sterol 12alpha-hydroxylase (CYP8B1), the key enzyme for synthesis of cholic acid (CA), and sterol 27-hydroxylase (CYP27), the initial enzyme in the alternative pathway. In the present study, the susceptibility of these three enzymes to dietary cholesterol and cholate, and the cholesterol lowering effect of taurine were determined in male C57BL/6 mice and Wistar rats. Both mice and rats were divided into 6 groups: control group (N), high cholesterol diet group (C), high cholesterol and cholate diet group (CB), and their 1% taurine-supplemented groups (NT, CT, CBT, respectively). After animals were fed with the respective diets for one week, the mRNA levels of CYP7A1 increased in the C-group compared with those of the N-group, and decreased in the CB-group compared with those of the C-group in both mice and rats. But the extent of decrease is different between the two species. CYP8B1 was also markedly repressed by cholate in mice, but not in rats. These results are consistent with the changes in serum and liver cholesterol concentrations. Taurine significantly increased CYP7A1 mRNA levels in the CBT-group compared with the CB-group in both animal models, with a subsequent decrease in serum and liver cholesterol levels and increase in fecal bile acid excretion. Up-regulated CYP8B1 was also observed after taurine supplementation in the CBT-group in mice. No increase in CYP7A1 was produced by taurine in the CT-group compared with that of the C-group in mice, although the changes of serum and liver cholesterol and fecal bile acids indicated taurine showed an efficient cholesterol lowering effect. In addition, CYP27 was induced in both C- and CB-groups of rats but not of mice, and no changes were produced by taurine. The overall results suggest that there are differences between mice and rats in susceptibility of the three enzymes to dietary cholesterol and cholate, and taurine induced CYP7A1 to produce its cholesterol-lowering effect only in the presence of cholate in the cholesterol diet.     

Fucoxanthin-rich seaweed extract suppresses body weight gain and improves lipid metabolism in high-fat-fed C57BL/6J mice

An ethanol extract of fucoxanthin-rich seaweed was examined for its effectiveness as a nutraceutical for body fat-lowering agent and for an antiobese effect based on mode of actions in C57BL/6J mice. Animals were randomized to receive a semi-purified high-fat diet (20% dietary fat, 10% corn oil and 10% lard) supplemented with 0.2% conjugated linoleic acid (CLA) as the positive control, 1.43% or 5.72% fucoxanthin-rich seaweed ethanol extract (Fx-SEE), equivalent to 0.05% or 0.2% dietary fucoxanthin for six weeks. Results showed that supplementation with both doses of Fx-SEE significantly reduced body and abdominal white adipose tissue (WAT) weights, plasma and hepatic triglyceride (TG), and/or cholesterol concentrations compared to the high-fat control group. Activities of adipocytic fatty acid (FA) synthesis, hepatic FA and TG synthesis, and cholesterol–regulating enzyme were also lowered by Fx-SEE supplement. Concentrations of plasma high-density lipoprotein-cholesterol, fecal TG and cholesterol, as well as FA oxidation enzyme activity and UCP1 mRNA expression in epididymal WAT were significantly higher in the Fx-SEE groups than in the high-fat control group. CLA treatment reduced the body weight gain and plasma TG concentration. Overall, these results indicate that Fx-SEE affects the plasma and hepatic lipid profile, fecal lipids and body fat mass, and alters hepatic cholesterol metabolism, FA synthesis and lipid absorption.     

Soyasaponins lowered plasma cholesterol and increased fecal bile acids in female golden Syrian hamsters

A study was conducted in hamsters to determine if group B soyasaponins improve plasma cholesterol status by increasing the excretion of fecal bile acids and neutral sterols, to identify group B soyasaponin metabolites, and to investigate the relationship between a fecal group B soyasaponin metabolite and plasma lipids. Twenty female golden Syrian hamsters, 11-12 weeks old and 85-125 g, were randomly assigned to a control diet or a similar diet containing group B soyasaponins (containing no isoflavones), 2.2 mmol/kg, for 4 weeks. Hamsters fed group B soyasaponins had significantly lower plasma total cholesterol (by 20%), non-high-density lipoprotein (HDL) cholesterol (by 33%), and triglycerides (by 18%) compared with those fed casein (P < 0.05). The ratio of total cholesterol to HDL cholesterol was significantly lower (by 13%) in hamsters fed group B soyasaponins than in those fed casein (P < 0.05). The excretion of fecal bile acids and neutral sterols was significantly greater (by 105% and 85%, respectively) in soyasaponin-fed hamsters compared with those fed casein (P < 0.05). Compared with casein, group B soyasaponins lowered plasma total cholesterol levels and non-HDL cholesterol levels by a mechanism involving greater excretion of fecal bile acids and neutral sterols. Hamsters fed group B soyasaponins statistically clustered into two fecal soyasaponin metabolite-excretion phenotypes: high excreters (n = 3) and low excreters (n = 7). When high and low producers of this soyasaponin metabolite were compared for plasma cholesterol status, the high producers showed a significantly lower total-cholesterol-to-HDL-cholesterol ratio compared with the low producers (1.38 +/- 0.7 vs. 1.59 +/- 0.13; P < 0.03). Greater production of group B soyasaponin metabolite in hamsters was associated with better plasma cholesterol status, suggesting that gut microbial variation in soyasaponin metabolism may influence the health effects of group B soyasaponins.     

Effect of coix on plasma, liver, and fecal lipid components in the rat fed on lard- or soybean oil-cholesterol diet

To determine the influence of dietary coix on lipid metabolism, the effect of coix on plasma, liver, and fecal lipid components was studied using Sprague-Dawley male rats. All rats were divided into four groups, and the rats of each group were fed the coix-lard diet, coix-soybean oil diet, or the respective control diets (containing 1% cholesterol each) for 27 days. Plasma and liver cholesterol levels in the coix-lard diet group significantly decreased as compared with those in the control group, whereas there was no effect on the fecal excretion of cholesterol. The decreases in the concentrated liver triglyceride and the increases in the fecal excretion of triglyceride were found in coix-soybean oil diet group. Moreover, liver and fecal phospholipid levels in both coix diet groups significantly increased. But there were no significant changes in plasma and fecal bile acids in either coix diet group. These results suggest the possibilities that coix may have an inhibitory action on cholesterol synthesis in liver, a facilitating effect on biliary excretion of triglyceride, and an acceleratory action on phospholipid synthesis in liver.     

Effects of soy protein on alcoholic liver disease in rats undergoing ethanol withdrawal

ObjectiveThis investigation attempted to clarify the effects of soy protein on alcoholic liver disease (ALD) in rats undergoing ethanol withdrawal.MethodsAlcoholic liver disease was induced in rats by administration of a low-carbohydrate ethanol liquid diet for 12 weeks, after which the ethanol was withdrawn and the rats were divided into two experimental groups: a control group (EC group) and a soy protein group (EP group) for 4 weeks.ResultsAfter the 12-week ALD-inducing period, the ethanol group had significantly higher hepatic lipid accumulation, oxidative stress and inflammation. We found that the EP group had significantly lower hepatic lipids, malondialdehyde, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, hydroxyproline levels and myeloperoxidase activity compared to the EC group. Moreover, the fecal total cholesterol and total lipids were higher in the EP group. Expression of the hepatic cytochrome P450 2E1 (CYP2E1) protein in the EP group was significantly lower than that in the EC group, and the hepatic peroxisome proliferator-activated receptor (PPAR) α and cytochrome P450 4A (CYP4A) protein expressions in the EP group were significantly higher than those in the EC group. In the histopathological analysis, we also found that soy protein ameliorated fat accumulation in the liver.ConclusionThese results suggest that soy protein may improve alcohol-induced lipid accumulation, oxidative stress and inflammation by decreasing proinflammatory cytokines and CYP2E1 protein expression and by increasing PPARα and CYP4A protein expressions and fecal lipid excretion, thereby producing beneficial effects on ALD during ethanol withdrawal.     

Hypocholesterolemic mechanism of Chlorella: Chlorella and its indigestible fraction enhance hepatic cholesterol catabolism through up-regulation of cholesterol 7alpha-hydroxylase in rats

Chlorella powder (CP) has a hypocholesterolemic effect and high bile acid-binding capacity; however, its effects on hepatic cholesterol metabolism are still unclear. In the present study, male Wistar rats were divided into four groups and fed a high sucrose + 10% lard diet (H), an H + 10% CP diet (H+CP), an H + 0.5% cholesterol + 0.25% sodium cholate diet (C), or a C + 10% CP diet (C+CP) for 2 weeks. CP decreased serum and liver cholesterol levels significantly in rats fed C-based diets, but did not affect these parameters in rats fed H-based diets. CP increased the hepatic mRNA level and activity of cholesterol 7alpha-hydroxylase (CYP7A1). CP increased hepatic HMG-CoA reductase (HMGR) activity in the rats fed H-based diets, but not in rats fed C-based diets. CP did not affect hepatic mRNA levels of sterol 27-hydroxylase, HMGR, low-density lipoprotein (LDL) receptor, scavenger receptor class B1, ATP-binding cassette (ABC) A1, ABCG5, or ABCB11. Furthermore, the effect of a 3.08% Chlorella indigestible fraction (CIF, corresponding to 10% CP) on hepatic cholesterol metabolism was determined using the same animal models. CIF also decreased serum and liver cholesterol levels significantly in rats fed C-based diets. CIF increased hepatic CYP7A1 mRNA levels. These results suggest that the hypocholesterolemic effect of CP involves enhancement of cholesterol catabolism through up-regulation of hepatic CYP7A1 expression and that CIF contributes to the hypocholesterolemic effect.     

A freshwater clam (Corbicula fluminea) extract improves cholesterol metabolism in rats fed on a high-cholesterol diet

The effect of a freshwater clam (Corbicula fluminea) extract (FCE) on cholesterol metabolism in rats fed on a high-cholesterol diet was investigated. When rats were fed various amounts of FCE in addition to the high-cholesterol diet for 2 wk, the serum and hepatic cholesterol levels were gradually reduced in a dose-dependent manner, as compared with the control group. The excretion of neutral sterols and bile acids into the feces was increased by feeding FCE. Several phytosterols were detected in the feces of rats fed on the FCE-containing diet. In addition, substantial amounts of phytosterols were found in FCE. Cholesterol 7alpha-hydroxylase (CYP7A1) mRNA in the liver of the rats fed on the FCE-containing diets was higher than that of rats fed on the high-cholesterol diets without FCE. These results may suggest that enhanced cholesterol degradation and the excretion of neutral sterols and bile acids contributed to the hypocholesterolemic effect of FCE observed in the hypercholesterolemic rats fed on the high-cholesterol diet.     

Effect of 3,4-di(OH)-cinnamate synthetic derivative on plasma and hepatic cholesterol level and antioxidant enzyme activities in high cholesterol-fed rats

The effect of 3,4-di(OH)-phenylpropionic acid (L-phenylalanine methyl ester) amide (SL-1063), a synthetic derivative of 3,4-di(OH)-cinnamate, on the cholesterol metabolism and antioxidant enzyme system was examined in rats. Diets that included either SL-1063 (0.046%, w/w) or lovastatin (0.02%, w/w) as a supplement, plus 1 g cholesterol/100 g diet were fed to rats ad libitum for 5 weeks. The total plasma cholesterol and triglyceride levels were significantly lowered by the SL-1063 supplement compared to the control group. Meanwhile, the levels of plasma HDL-cholesterol and ratio of HDL-cholesterol/total cholesterol (%) were significantly higher in the SL-1063 group than in the control group. However, the lovastatin supplement did not affect the plasma lipid level. The hepatic cholesterol level and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity were significantly lowered in the lovastatin group compared to the SL-1063 group; however, the hepatic triglyceride level did not differ among the groups. The activity of hepatic acyl CoA: cholesterol acyltransferase (ACAT), the enzyme that catalyzes hepatic cholesterol esterification, was significantly lower in the lovastatin and SL-1063 groups than in the control group. Furthermore, the SL-1063 supplement elevated the excretion of fecal sterols. As regards the hepatic antioxidant enzyme system, the superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities were all significantly higher in the SL-1063 group compared to the control group, whereas only the GR activity was significantly increased by the lovastatin supplement. No marked difference in the GSH levels and glucose-6-phosphate dehydrogenase (G6PD) activities was observed among the groups. The levels of plasma and hepatic thiobarbituric acid reactive substances (TBARS) were lowered by the SL-1063 supplement compared to the control group. Accordingly, the current results suggest that SL-1063, a synthetic derivative of 3,4-di(OH)-cinnamate, is effective in lowering the plasma lipids and improving the antioxidant enzyme system.     

Alteration of biliary ursodeoxycholic acid in guinea pig during early stages of cholestyramine feeding

The effects of cholestyramine feeding on biliary ursodeoxycholic acid, fecal excretion of bile acids and neutral sterols on cholesterol 7α-hydroxylase and hepatic HMG-CoA reductase were examined in the guinea pig. In the bile there was a 57% decrease in the concentration of ursodeoxycholic acid while an increase was observed in the concentration of chenodeoxycholic acid. Cholestyramine feeding for ten days resulted in a decrease in plasma cholesterol levels and an increase in both hepatic HMG-CoA reductase and cholesterol 7α-hydroxylase activities. The fecal excretion of both bile acids and neutral sterols was significantly increased.     

Bioavailability of Trace Elements in Beans and Zinc-Biofortified Wheat in Pigs

The objectives of this experiment were to study bioavailability of trace elements in beans and wheat containing different levels of zinc and to study how the water solubility of trace elements was related to the bioavailability in pigs. Three wheat and two bean types were used: wheat of Danish origin as a control (CtrlW), two Turkish wheat types low (LZnW) and high (HZnW) in zinc, a common bean (Com), and a faba bean (Faba). Two diets were composed by combining 81?% CtrlW and 19?% Com or Faba beans. Solubility was measured as the trace element concentration in the supernatant of feedstuffs, and diets incubated in distilled water at pH?4 and 38°C for 3?h. The bioavailability of zinc and copper of the three wheat types and the two bean-containing diets were evaluated in the pigs by collection of urine and feces for 7?days. The solubility of zinc was 34?C63?%, copper 18?C42?%, and iron 3?C11?%. The zinc apparent digestibility in pigs was similar in the three wheat groups (11?C14?%), but was significantly higher in the CtrlW+Faba group (23?%) and negative in the CtrlW+Com group (?30?%). The apparent digestibility of copper was higher in the HZnW (27?%) and CtrlW+Faba (33?%) groups than in the CtrlW (17?%) and LZnW (18?%) groups. The apparent copper digestibility of the CtrlW+Com diet was negative (?7?%). The solubility and digestibility results did not reflect the concentration in feedstuffs. The in vitro results of water solubility showed no relationship to the results of trace mineral bioavailability in pigs.     

Cholesterol-lowering effects of dietary pomegranate extract and inulin in mice fed an obesogenic diet

BackgroundIt has been demonstrated in animal studies that both polyphenol-rich pomegranate extract (PomX) and the polysaccharide inulin, ameliorate metabolic changes induced by a high-fat diet, but little is known about the specific mechanisms.ObjectiveThis study evaluated the effect of PomX (0.25%) and inulin (9%) alone or in combination on cholesterol and lipid metabolism in mice.MethodsMale C57BL/6 J mice were fed high-fat/high-sucrose [HF/HS (32% energy from fat, 25% energy from sucrose)] diets supplemented with PomX (0.25%) and inulin (9%) alone or in combination for 4 weeks. At the end of intervention, serum and hepatic cholesterol, triglyceride levels, hepatic gene expression of key regulators of cholesterol and lipid metabolism as well as fecal cholesterol and bile acid excretion were determined.ResultsDietary supplementation of the HF/HS diet with PomX and inulin decreased hepatic and serum total cholesterol. Supplementation with PomX and inulin together resulted in lower hepatic and serum total cholesterol compared to individual treatments. Compared to HF/HS control, PomX increased gene expression of Cyp7a1 and Cyp7b1, key regulators of bile acid synthesis pathways. Inulin decreased gene expression of key regulators of cholesterol de novo synthesis Srebf2 and Hmgcr and significantly increased fecal elimination of total bile acids and neutral sterols. Only PomX in combination with inulin reduced liver and lipid weight significantly compared to the HF/HS control group. PomX showed a trend to decrease liver triglyceride (TG) levels, while inulin or PomX-inulin combination had no effect on either serum or liver TG levels.ConclusionDietary PomX and inulin supplementation decreased hepatic and serum total cholesterol by different mechanisms and the combination leading to a significant enhancement of the cholesterol-lowering effect.     

A Freshwater Clam (Corbicula fluminea) Extract Improves Cholesterol Metabolism in Rats Fed on a High-Cholesterol Diet

The effect of a freshwater clam (Corbicula fluminea) extract (FCE) on cholesterol metabolism in rats fed on a high-cholesterol diet was investigated. When rats were fed various amounts of FCE in addition to the high-cholesterol diet for 2 wk, the serum and hepatic cholesterol levels were gradually reduced in a dose-dependent manner, as compared with the control group. The excretion of neutral sterols and bile acids into the feces was increased by feeding FCE. Several phytosterols were detected in the feces of rats fed on the FCE-containing diet. In addition, substantial amounts of phytosterols were found in FCE. Cholesterol 7α-hydroxylase (CYP7A1) mRNA in the liver of the rats fed on the FCE-containing diets was higher than that of rats fed on the high-cholesterol diets without FCE. These results may suggest that enhanced cholesterol degradation and the excretion of neutral sterols and bile acids contributed to the hypocholesterolemic effect of FCE observed in the hypercholesterolemic rats fed on the high-cholesterol diet.     

Sterols in hardening winter wheat

The main sterols in winter wheat crowns and roots were sitosterol and campesterol, with significant amounts of stigmasterol and traces of cholesterol. The main groups of sterol-containing lipids were free sterols, steryl glucosides, steryl esters and esterified steryl glucosides. Sterol analysis within each group showed little difference between them. Steryl esters were relatively rich in cholesterol and poor in stigmasterol. Free sterols were rich in stigmasterol. Low temperature caused an increase in sterol content but had little effect on sterol composition and sterol to lipid P ratio. There was some increase in steryl esters and some decrease in free sterols. Cholesterol and stigmasterol decreased in the steryl ester and free sterol fractions, respectively. There was little evidence for involvement of sterols in winter wheat frost hardening.     

Cholesterol-lowering effects of maitake (Grifola frondosa) fiber, shiitake (Lentinus edodes) fiber, and enokitake (Flammulina velutipes) fiber in rats

The effects of mushroom fibers on serum cholesterol and hepatic low-density lipoprotein (LDL) receptor mRNA in rats were investigated. Rats were fed a cholesterol-free diet with 50 g/kg cellulose powder (CP), 50 g/kg maitake (Grifola frondosa) fiber (MAF), 50 g/kg shiitake (Lentinus edodes) fiber (SF), or 50 g/kg enokitake (Flammulina velutipes) fiber (EF) for 4 weeks. There were no significant differences in the body weight, food intake, liver weight, cecum weight, and cecum pH among the groups. Cecal acetic acid, butyric acid, and total short-chain fatty acid (SCFA) concentrations in the SF and EF groups were significantly higher than those in the other groups. The serum total cholesterol concentration in the CP group was significantly higher than that in the MAF and EF groups. The very LDL (VLDL) + intermediate-density lipoprotein (IDL) + LDL-cholesterol concentration in the CP group was significantly higher than that in the MAF, SF, and EF groups, whereas the high-density lipoprotein (HDL)-cholesterol concentration in the EF group was significantly lower than that in the other groups at the end of the 4-week feeding period. The hepatic LDL receptor mRNA level in the EF group was significantly higher than that in the CP group. The fecal cholesterol excretion in the MAF, SF, and EF groups was significantly higher than that in the CP group. The results of this study demonstrate that MAF and EF lowered the serum total cholesterol level by enhancement of fecal cholesterol excretion, and in particular, by enhancement of hepatic LDL receptor mRNA in EF group.     

Comparison of Cardiovascular Risk Factors in Obese Blacks and Whites

Blacks are known to have higher blood pressure levels, a higher prevalence of hypertension, and higher body weights than whites. However, the interrelationships of these and other cardiac risk factors have not been analyzed in an obese population. We compared blood pressure (BP) and lipid levels in 174 obese blacks and 939 obese white patients who were entering a weight loss program; we also assessed the effects of weight loss on these factors. Prevalence of treated hypertension was similar in blacks and whites (28% vs. 25%, respectively). In patients not taking BP medication, black women weighed more (108 kg) than white women (102 kg) and black and white males' weights were similar (135 kg vs. 131 kg). Systolic and diastolic BP were similar in black and white women; black males had similar SBP but a significantly lower DBP than white males (83 mmHg vs. 89 mmHg, respectively). Lipid levels were similar in black and white women except black women had lower triglycerides (1.30 mmol/L) than white women (1.58 mmol/L, p<0.05); and black males compared to white males had significantly lower total cholesterol (4.76 mmol/L vs. 5.56 mmol/L), LDL-cholesterol (3.15 mmol/L vs. 3.52 mmol/L) and triglycerides (1.31 mmol/L vs. 2.17 mmol/L, p<0.05). Adult-onset obesity adversely affected a number of cardiovascular risk factors in whites, but not in blacks. Blacks lost significantly less weight (?13 kg) than whites (?19 kg). However, controlling for the difference in weight loss, blacks sustained comparable improvement in lipids and blood pressure, except for TC/HDL-C (whites improved significantly more, ?0.36 kg/m2, than blacks, 0.03 kg/m2). Thus, the impact of obesity on cardiovascular risk factors seems ameliorated in blacks com-pared to whites.     

Hypocholesterolemic Mechanism of Chlorella: Chlorella and Its Indigestible Fraction Enhance Hepatic Cholesterol Catabolism through Up-Regulation of Cholesterol 7α-Hydroxylase in Rats

Chlorella powder (CP) has a hypocholesterolemic effect and high bile acid-binding capacity; however, its effects on hepatic cholesterol metabolism are still unclear. In the present study, male Wistar rats were divided into four groups and fed a high sucrose + 10% lard diet (H), an H + 10% CP diet (H+CP), an H + 0.5% cholesterol + 0.25% sodium cholate diet (C), or a C + 10% CP diet (C+CP) for 2 weeks. CP decreased serum and liver cholesterol levels significantly in rats fed C-based diets, but did not affect these parameters in rats fed H-based diets. CP increased the hepatic mRNA level and activity of cholesterol 7α-hydroxylase (CYP7A1). CP increased hepatic HMG-CoA reductase (HMGR) activity in the rats fed H-based diets, but not in rats fed C-based diets. CP did not affect hepatic mRNA levels of sterol 27-hydroxylase, HMGR, low-density lipoprotein (LDL) receptor, scavenger receptor class B1, ATP-binding cassette (ABC) A1, ABCG5, or ABCB11. Furthermore, the effect of a 3.08% Chlorella indigestible fraction (CIF, corresponding to 10% CP) on hepatic cholesterol metabolism was determined using the same animal models. CIF also decreased serum and liver cholesterol levels significantly in rats fed C-based diets. CIF increased hepatic CYP7A1 mRNA levels. These results suggest that the hypocholesterolemic effect of CP involves enhancement of cholesterol catabolism through up-regulation of hepatic CYP7A1 expression and that CIF contributes to the hypocholesterolemic effect.     

Cholesterol metabolism during ketoconazole treatment in man

Ketoconazole, an antifungal antibiotic, inhibits cholesterol synthesis by blocking demethylation of lanosterol. Effects of this inhibition were studied on serum cholesterol, lipoproteins and cholesterol precursors, biliary lipid composition, and fecal steroid elimination in five patients with prostate cancer treated with large doses of ketoconazole. The serum level of total cholesterol fell by 27%, that of LDL cholesterol by 41% and that of LDL apoB by 32% with ketoconazole alone; the fall in the total cholesterol level of a patient treated with ketoconazole-cholestyramine was 65%. Serum contents of free lanosterol and dihydrolanosterol increased up to 250 times, yet the total concentrations remained less than 2 mg/dl. Of the other cholesterol precursor sterols only those with delta 8-double bond increased several times, indicating that in addition to 14 alpha-demethylation, ketoconazole also interfered with metabolism of later intermediary sterols to some extent. Compared with serum sterols, lanosterols were enriched in biliary and fecal sterols up to 10-20 times. Fecal lanosterol output increased from 12 to 247 mg/day, and comprised over 20% fecal steroids of endogenous origin. Bile acid synthesis was significantly decreased, the proportion of chenodeoxycholic acid being markedly reduced in both biliary and fecal bile acids. Cholesterol absorption appeared to decrease yet fecal neutral sterol output and cholesterol synthesis were unchanged and the overall sterol synthesis was increased. It thus appears that ketoconazole inhibits cholesterol elimination as bile acids. However, by blocking 14 alpha-demethylation, it results in effective drainage of sterol nucleus as lanosterols into bile and feces, which, in turn, is associated with a marked reduction in low density lipoprotein (LDL) cholesterol level probably through activation of hepatic LDL apoB receptors.     

Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice

As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B1-/-) fail to produce cholic acid (CA), upregulate their bile acid synthesis, reduce the absorption of dietary cholesterol and, after cholesterol feeding, accumulate less liver cholesterol than wild-type (CYP8B1+/+) mice. In the present study, cholesterol-enriched diet (0.5%) or administration of a synthetic liver X receptor (LXR) agonist strongly upregulated CYP7A1 expression in CYP8B1-/- mice, compared to CYP8B1+/+ mice. Cholesterol-fed CYP8B1-/- mice also showed a significant rise in HDL cholesterol and increased levels of liver ABCA1 mRNA. A combined CA (0.25%)/cholesterol (0.5%) diet enhanced absorption of intestinal cholesterol in both groups of mice, increased their liver cholesterol content, and reduced their expression of CYP7A1 mRNA. The ABCG5/G8 liver mRNA was increased in both groups of mice, but cholesterol crystals were only observed in bile from the CYP8B1+/+ mice. The results demonstrate the cholesterol-sparing effects of CA: enhanced absorption and reduced conversion into bile acids. Farnesoid X receptor (FXR)-mediated suppression of CYP7A1 in mice seems to be a predominant mechanism for regulation of bile acid synthesis under normal conditions and, as confirmed, able to override LXR-mediated mechanisms. Interaction between FXR- and LXR-mediated stimuli might also regulate expression of liver ABCG5/G8.