Cardiovascular diseases (CVDs) are the most important cause of death in the world, including China. Hyperchol- esterolemia is strongly associated with coronary heart disease . HDL-C can prevent CVDs such as arterio- sclerosis by removing cholesterol from the blood stream, whereas LDL-C causes accumulation of cholesterol in blood vessels. TC/HDL-C and LDL-C/HDL-C ratios are recognized as two important indicators of CVDs risk with greater predictive value than isolated parameters used independently . The higher the ratios are, the greater the CVDs risk is. Therefore, reduction of serum total cholesterol (TC) and LDL-C and increase of HDL- C may be an important treatment option for CVDs. Probiotics are defined as “living microbial supplements that beneficially affect the host animals by improving its intestinal microbial balances” . In this study, we used two NS lactobacillus strains isolated from natural fermented dairy products collected from grassland in Inner Mongolia of China, Lactobacillus plantarum NS5 and Lactobacillus delbrueckii subsp. bulgaricus NS12. We found that NS5 strain could significantly reduce the serum TC and LDL-C levels (reduced by 18.11% and 33.33%, respectively) compared to rats fed with high- cholesterol diet by the end of 6 weeks. Similar results were previously reported in other Lactobacillus plantarum strains [12,13]. NS12 strain also reduced the levels of TC and LDL-C (reduced by 12.83% and 22.44%, respectively), but there were no statistical significances compared with HC group. However, there was also no significant differ- ence with NS5 strains. They all didn’t obviously influence HDL-C levels. Meanwhile, both NS5 and NS12 strains sig- nificantly reduced the TC/HDL-C (23.25% vs. 15.41%) and LDL-C/HDL-C ratios (37.14% vs. 23.81%) and NS5 strain seemed more effective than NS12 strain. Liver cholesterol levels were also examined. NS5 and NS12 strains all obvi- ously decreased the cholesterol levels in liver compared
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Little is known regarding the molecular mechanisms underlying the effects of testosterone deficiency on choles- terol metabolism. Cholesterol homeostasis is controlled by coordinated changes in the expression of multiple genes in- volved in cholesterol biosynthesis, uptake, and efflux . It was well known that LXRα plays a critical role in cholesterol metabolism  and that LXR α expression increases choles- terol efflux by regulating its target genes. CYP7A1 is one of the most important target genes of LXRα and was identified as the rate-limiting enzyme in bile acid-synthesis for choles- terol elimination . In the present study, we observed that castration had no effect on the liver mRNA expression levels of LXR α or CYP7A1 in pigs. These results suggested that the increased cholesterol levels observed in CM + HFC pigs may not have resulted from enhanced cholesterol efflux through the LXRα-CYP7A1 pathway. HMGCR is the rate- limiting enzyme mediating de novo cholesterol synthesis . Similarly, hepatic HMGCR activity and mRNA expres- sion were not changed by castration and testosterone re- placement. Thus, testosterone deficiency might not influence the de novo synthesis of cholesterol in the livers of CM + HFC pigs. It is well known that LDLR is a crucially important modulator of plasma LDL-cholesterol levels in humans and animals. Increased LDLR expression was shown to result in reduced serum LDL-cholesterol levels . We found that LDLR mRNA expression and protein levels were significantly decreased in the livers of CM + HFC pigs, compared to IM + HFC and CM + HFC + T pigs. This agreed with our findings that CM + HFC pigs showed a sig- nificant increase in both serum LDL-cholesterol and TC levels. Moreover, these findings suggest that one of the mechanisms through which testosterone deficiency can in- crease serum cholesterol levels in CM + HFC pigs is by de- creasing LDLR expression, thus inhibiting the removal of LDL-cholesterol from the circulation. In animals, hepatic LDLR and HMGCR are transcriptionally regulated by SREBP2 . However, in the present study hepatic SREBP2 mRNA expression was not influenced by castration and tes- tosterone replacement, suggesting that other mechanisms may participate in the regulation of LDLR. Previous studies demonstrated that hepatic LDLR mRNA transcription can be suppressed by a high-cholesterol diet [39-41]. Moreover, dietary cholesterol has been reported to increase hepatic TG and cholesterol stores, which in turn suppresses hepatic LDLR mRNA levels . Thus, the reduced hepatic LDLR
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lipid indices (Table 4). The CHO rats fed 1% of the cholesterol diet exhibited a significant increase (P < 0.05) in triglyceride level compared with the other groups. The CON and COQ groups fed no choles- terol diet showed a significantly higher (p < 0.05) HDL-C compared with the CHO and CHCQ groups fed 1% of cholesterol. The CHO group also showed much higher (P < 0.05) ratios of TC/HDL-C and LDL- C/HDL-C than the CON group, indicating that 1% of cholesterol supplement to diet resulted in a greater the atherogenic risks in rats. However, 0.5% of CoQ 10
Male C57BL/6 J mice (3 weeks old) were housed at the Korea Food Research Institute (KFRI) in a climate- controlled environment (24 °C at 50% relative humidity) with a 12 h light/dark cycle. After 1 week of adaptation, the mice were randomly divided into four groups ( n = 8): N (Normal diet), HC (high-cholesterol diet), YL (HC + 1% YE), and YH (HC + 5% YE). D12336 diet (high-cholesterol diet, Purified diet to match Paigen’s atherogenic rodent diet, Research Diets, Inc.) was used as HC. The composition of the high cholesterol diet was as follow: 46% carbohydrate, 16% fat, 21% protein, 12.5% cholesterol, 0.5% cholic acid, mineral mixture and vitamin mixture (source of carbohy- drate = maltodextrin, sucrose and corn starch; source of fat = soybean oil, cocoa butter and coconut oil; source of protein = casein, soy protein and DL-methionine, source of mineral mixture = calcium carbonate, sodium chloride, po- tassium citrate; vitamin mixture = choline bitartrate). The mice were fed these diets for 10 weeks with free access to autoclaved tap water in cages. The total daily intake and weight of mice were recorded every week for up to 10 weeks. At the end of the experiment, animals were sacrificed to collect their blood and liver tissue samples, which were then stored at − 70 °C. Our experimental proto- col was approved by the Institutional Animal Care and Use Committee of the Korea Food Research Institute.
The present study investigated the effect of starvation-refeeding status on cholesterol metabolism in rats fed a high-cholesterol diet or a cholesterol-free diet. Twenty male and 20 female Donryu rats (age 5 weeks) were fed a cho- lesterol-free diet for 14 days. Then the male and female rats were each divided into two groups: feeding and starva- tion-refeeding groups. The feeding groups were fed the experimental diet for 3 days, and the starvation-refeeding groups fasted for 2 days followed by 3 days of feeding. Half of each of groups was fed a cholesterol-free diet and the other half was fed a high-cholesterol diet. Starvation-refeeding significantly increased the plasma free cholesterol and HDL-cholesterol concentrations in both the high-cholesterol-diet-fed rats and the cholesterol-free-diet-fed rats. In the female rats, plasma total cholesterol and cholesteryl ester concentrations were significantly higher in the high-cholesterol groups than in the cholesterol-free groups, whereas TG concentration and total cholesterol/TG ratio were not significantly different among all of the groups. Liver total cholesterol and cholesteryl ester were significantly higher in the high-cholesterol groups than in the cholesterol-free groups in both male and female rats. These results suggest that starvation-refeeding affected cholesterol metabolism at least in part. The reactivity of the cholesterol me- tabolism may be different between male and female rats.
ness index (Fig. 3b, column 2 vs. 4; P > 0.1) between the high-cholesterol diet alone group and the group treat- ed with both high-cholesterol diet and MoPn infection. The nine-month observation time point was chosen based on an earlier pilot experiment in which mice from various treatment groups were sacrificed at three, six, and nine months for aortic lesion evaluation. We found that none of the mice sacrificed at three months displayed any obvious atherosclerosis lesions in their aorta (data not shown). At six months, significant lesions were detected in the aorta of mice fed the high-cholesterol diet. None of the mice fed the normal chow displayed any obvious aor- tic lesions (Fig. 3c). However, there was no significant dif- ference in lesion area index between the high-cholesterol diet alone and the high-cholesterol diet plus AR39 infec- tion groups (P = 0.852). Sera from the AR39-infected mice displayed high titers of anti AR39 organism antibodies (>1:10,000; data not shown), suggesting that these mice were successfully infected with the AR39 organisms. Only by nine months did mice fed the high-cholesterol diet plus AR39 infection display much more severe aortic lesions than the mouse fed the high-cholesterol diet alone (Fig. 3). These preliminary results suggest that the high-cho- lesterol diet initiated the aortic atherosclerotic lesions, whereas the C. pneumoniae infection greatly exacerbated the lesions. However, the relatively small sample size may necessitate further experiments to confirm these results. Both AR39 and MoPn antigens were detected in aorta of mice infected intranasally with the corresponding chlamydial strains. It is possible that the AR39 or MoPn organisms may have a different capacity to reach the aortic tissue after a res- piratory infection. To test the hypothesis, a mouse anti- chlamydial lipopolysaccharide (LPS) antibody was used to detect the chlamydial antigen in aortic cross-sections. The reasons for choosing this antibody
On the third day after delivery of the hamsters to the insti- tution, their diet was switched from the standard rodent chow to AIN-93 M diet for 7 days. The AIN-93 M diet has a balance of essential nutrients and is suitable for both long- and short-term studies with laboratory rodents. While the control group (C) was given the AIN-93 M diet, all other experimental diets were modified from the basic AIN-93 M diet. The high cholesterol diet (HF) was pre- pared by adding 7.5% cocoa butter and 1.25% cholesterol to the AIN-93 M diet (Table 1) . In addition, 0.08 g/kg feed of fish oil from menhaden fish (Sigma-Aldrich China, Inc., Shanghai, China) and 0.011 g/kg feed of spirulina (Fuqing King Dnarmsa Spirulina Co., Ltd, FuQing, China) were subsequently added by small amounts with continu- ous stirring to the AIN-93 M diet to constitute the fish oil (FO) and spirulina (SP) diets, respectively. The same doses of fish oil and spirulina were added together to either the AIN-93 M or to the HF diet to form the diets for com- bined treatments (SF and HF + SF). Fatty acid composi- tions in menhaden fish oil (Sigma-Aldrich China) are composed of approximately 80% identified fatty acids, including 6-9% myristic acid (14:0), 15-20% palmitic acid (16:0), 9-14% palmitoleic acid (16:1), 3-4% stearic acid (18:0), 5-12% oleic acid (18:1), < 3% linoleic acid (18:2), < 3% linolenic acid (18:3), 2-4% octadecatetraenoic acid (18:4), < 3% arachidonic acid (20:4), 10-15% eicosa- pentaenoic acid (EPA, 20:5), and 8-15% docosahexaenoic acid (DHA, 22:6), and 20% unidentified fatty acids. Spiru- lina powder (Fuqing King Dnarmsa Spirulina Co., Ltd) primarily contains 65.2% protein, 6.6% water, 6.7% ash, 13.7% crude ohycocyanin, 1241 mg/100 g chlorophyll, and 463 mg/100 g total carotenoids.
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Apart from lowering lipid composition in the aorta, C. domestica also reduced the cholesterol depositions in the aorta of high cholesterol diet animals. These results indicate that addition of C. domestica to the high choles- terol diet of guinea pigs prevented a build up of lipids in the aorta. It is possible that C. domestica may project these effects through the reduction of aorta cholesterol level which may simultaneously lower the levels of trig- lyceride and phospholipid in the aorta. Dixit et al. (1988) have shown that the hypocholesterolemic effect of eth- anolic extract of C. domestica in the serum was followed by the lowering of triglyceride and phospholipid levels in the serum  and it has been repeatedly reported that C. Figure 3
Feedback regulation of cholesterol biosynthesis is mediated by membrane-bound transcription factors designated sterol regulatory element–binding proteins (SREBP)-1 and -2. In sterol-deprived cultured cells, SREBPs are released from membranes by a proteolytic process that is stimulated by SREBP cleavage–activating protein (SCAP), a membrane protein containing a sterol-sensing domain. Sterols sup- press SREBP cleavage by blocking the action of SCAP, thereby decreasing cholesterol synthesis. A point mutation in SCAP(D443N) causes resistance to sterol suppression. In this article, we produced transgenic mice that express mu- tant SCAP(D443N) in liver. In these livers the nuclear con- tent of SREBP-1 and -2 was increased, mRNAs encoding proteins involved in uptake and synthesis of cholesterol and fatty acids were elevated, and the livers were engorged with cholesteryl esters and triglycerides enriched in monounsat- urated fatty acids. When the mice were challenged with a high cholesterol diet, cleavage of SREBP-1 and -2 was re- duced in wild-type livers and less so in transgenic livers. We conclude that SCAP(D443N) stimulates proteolytic process- ing of native SREBPs in liver and decreases the normal ste- rol-mediated feedback regulation of SREBP cleavage, sug- gesting a central role for SCAP as a sterol sensor in liver. ( J. Clin. Invest. 1998. 102:2050–2060.) Key words: cholesterol •
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The effect of nicardipine on fasting plasma lipid profiles was studied in rabbits given a 2% cholesterol diet. Twenty four New Zealand White rabbits (2.2 - 2.8 kg) were divided into 3 groups. Group 1 (control) was fed a normal diet, group II (HC) was fed a 2% cholesterol diet and group III (HC+NICA) was fed a 2% cholesterol diet with nicardipine treatment (0.5mg kg -1 body weight twice daily intramuscularly for 10
Sex hormones affect may many facets of lipid metabol- ism through interactions with other regulators. Apolipo- protein E (apoE) and lipoprotein lipase (LPL), two important mediators in lipoprotein metabolism, are sig- nificantly affected by sex hormones because male and fe- male animals exhibit different lipoprotein profiles and response to a cholesterol diet and atherosclerosis when these two genes are overexpressed [18, 19]. Endothelial lipase (EL) was originally cloned from endothelial cells [20, 21], but EL is also expressed in liver, lung, thyroid, and kidney [22, 23]. Although EL, LPL, and hepatic lip- ase (HL) hydrolyze both triglycerides (TG) and phospho- lipids (PL) in the lipoproteins, they show different substrate selectivity. EL exhibits high phospholipase activity in high-density lipoproteins (HDL) but low triglyceride lipase activity, whereas LPL and HL mainly exercise TG lipase activity [24, 25]. Previous studies have shown that EL mediates HDL-cholesterol (HDL-C) levels along with VLDL levels [21, 26]. Re- cently, we found that expression of hepatic EL showed a significant influence on plasma lipids and lipoprotein metabolism . Interestingly, increased hepatic expression of EL inhibits cholesterol diet–in- duced hypercholesterolemia and protects against ath- erosclerosis in male Tg rabbits but not in female Tg rabbits. This finding prompted us to envision that there is an interaction between EL and sex hormones thereby influencing lipoprotein metabolism and ath- erosclerosis. To investigate this issue, we compared the lipoprotein features in male and female rabbits after castration. Our current study showed that gen- der differences in lipid metabolism and atherosclerosis observed in EL Tg rabbits are dependent on the pres- ence of androgens but not estrogens.
To analyse the individual effects of pioglitazone, quer- cetin, and hydroxy citric acid on the liver and on nor- mal metabolic activities, we studied three drug control groups. Pioglitazone treatment (group 3; pioglitazone control) in conjunction with the standard diet did not produce a significant effect on total cholesterol, esterified cholesterol, phospholipids, and FFA concentrations but resulted in a significant reduction in free cholesterol and triglyceride levels, compared with the control rats (group 1). This result could be attributed to the hypoglycaemic drug pioglitazone, which modulates the levels of lipids. 37
tory chow 5001, Purina Laboratories, St Louis, MO) and water for two weeks to allow adaptation to the environment. Baseline values of serum total cholesterol were measured at the end of two weeks in hamsters that were deprived of food overnight. Further, these basal serum total cholesterol values were used to assign animals into four groups using a randomized block design. The control group continued to be fed the reference diet 5001. Each of the other groups (n = 8) was from then onwards fed a grain-based, hyper- cholesterolemic chow diet (Modified LabDiet laboratory rodent diets with added cholesterol and 6% coconut oil as saturated fat, Purina Laboratories, see Table 1), with free access to water for five weeks. Diet consumption and body weight were measured every 10 days. Food efficiency ratio was computed as g body weight gain/g feed intake. Blood samples were collected once every 14 days from food-deprived hamsters (14 hours) that has been mildly sedated using 3 µ L of 5 mg/mL acepromazine. Briefly, after immobilizing the hamster, approximately 150 µ L of blood was collected from the lateral saphenous vein which runs dorsally and then laterally over the tarsal joint with a sterile 23 gauge/25 mm needle, into Microtainer ® serum separator
Nutrition during pregnancy can impact on the susceptibility of the offspring to cardiovascular disease. Postnatal consumption of trans fatty acids (TFA), associated with partially hydrogenated vegetable oil (PHVO), increases the risk of atherosclerosis, while evidence for those trans fatty acids associated with ruminant-derived dairy and meat remain equivocal. Here, we investigate the impact of maternal consumption of dietary PHVO (P) and ruminant milk fat (R) on the development of atherosclerosis in their offspring, using the transgenic apoE*3 Leiden mouse. Dams were fed either chow (C) or one of three high fat diets: a diet reflecting the saturated fatty acid content of a ‘Western’ diet (W) or one enriched with either P or R. Diets were fed during either pregnancy alone or pregnancy and lactation. Weaned offspring were then transferred to an atherogenic diet for twelve weeks. Atherosclerosis was assessed as lipid staining in cross-sections of the aorta. There was a significant effect of maternal diet during pregnancy on development of atherosclerosis (p=0.013) in the offspring with those born of mothers fed R or P during pregnancy displaying smaller lesions that those fed C or W. This was not associated with changes in total or lipoprotein cholesterol. Continuing to feed P during lactation increased atherosclerosis compared to that seen in offspring of dams fed P only during pregnancy (p<0.001). No such effect was seen in those from mothers fed R (p=0.596) or W (p=901). We conclude that dietary TFA have differing effects on cardiovascular risk at different stages of the lifecycle.
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polyunsaturated to saturated fatty acids (P/S) for different groups of subjects were 0.25, 0.4, 0.8, or 2.5. 750 and 1,500 mg/d of cholesterol were added to the basal diets as 3 and 6 eggs, respectively. Total cholesterol and LDL cholesterol were lower in all subjects on the basal diets than on the ad lib. diets. Addition of 750 mg cholesterol to the diet with P/S = 0.25-0.4 raised LDL cholesterol by 16 +/- 14 mg/dl to 115% of basal diet values (n = 11, P less than 0.01); 1,500 mg increased LDL cholesterol by 25 +/- 19 mg/dl to 125% (n = 9, P less than 0.01). On the diet with P/S = 0.8, 750 mg produced insignificant increases in LDL cholesterol, but 1,500 mg produced increases of 17 +/- 22 mg/dl to 115% of basal (n = 6, P less than 0.02). On the P/S = 2.5 diet, neither 750 nor 1,500 mg produced significant changes. Thus, both the cholesterol […]
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reductase [17, 18]. Thus, to inhibit the HMG- CoA reductase expression has been a major strategy to lower the plasma cholesterol [19, 20]. It has been shown that plant extracts and spices are able to reduce the cholesterol synthesis by inhibiting HMG-CoA reductase expression . In the present study, our results also showed the HMG-CoA reductase expression increased significantly in the liver of CL group, but supplement with capsaicin markedly reduced the HMG-CoA reductase expression (Figure 6). It is indicated that capsaicin is able to inhibit the endogenous cholesterol synthesis in the liver. Generally, the cholesterol may enter the bile duct along with the bile or be transformed into bile acid which is then excreted. CYP7A1 is a rate-limit- ing enzyme in the synthesis of bile acid, and to
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subsequently challenged with a diet containing 0.5% cholesterol, cholestyramine-pretreated pigeons exhibited significantly lower serum cholesterol level when compared with controls and this "hyporesponder" behavior persisted throughout the study period. Furthermore, the aorta of cholestyramine-treated animals exhibited significantly (a) lower prevalence and severity of atherosclerosis and (b) lower cholesterol content. These studies demonstrate for the first time that enhancement of cholesterol catabolism in early life improves resistance to diet-induced atherosclerosis in later life in this avian model.
To study the pathogenesis of cholesterol gallstones, we fed 24 adult male prairie dogs a high cholesterol, egg yolk diet. 13 control animals received a cholesterol-free diet. All animals fed the egg yolk diet formed multiple gallstones in 2-6 months' time. These stones contained cholesterol, 77±14% by dry weight. No stones ocurred in the control group. The egg yolk-fed animals developed bile of altered chemical composition. The cholesterol concentration of hepatic and gallbladder bile increased significantly. The molar ratios of bile acid/cholesterol and phospholipid/cholesterol decreased in hepatic and gallbladder bile. The predominant bile acid shifted from cholic acid, 78% of the total bile acids, to
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Lipid accumulation was further investigated to explore the anti-obesity effect of GP on mice. HFD intake significantly increased the total cholesterol (TC) and triglyceride (TG) concentration in the liver. GP intake had no significant impact on liver weight (Table 2 and Figure 2). However, the GP and GP extract groups had significantly decreased levels of hepatic TC and TG. This effect was most marked in the 1% GP extract group, whose TC and TG levels (190 and 260 mg/dL, respectively) were far lower than those of the HFD group (257 and 388 mg/dL, respectively). In contrast, there was no significant difference in serum levels of either TC or high-density lipoprotein-cholesterol (HDL-C) among any of the groups on the HFD. Serum TG concentrations significantly increased in the GP intake group (0.3% GP extract group: p < 0.05; 1% GP extract group: p < 0.01) (Table 2 and Figure 3).
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Angiotensin II (AII) is an important regulator of cardiovascular function. The ability to reduce level of AII with orally effective ACE inhibitor represents an important advance in treatment of hypertension. The ACE inhibitors appear to confer a special advantage in the treatment of patient with diabetes, slowing the development and progression of diabetic glomerulopathy. [10 ] ACE inhibitor decreases the production of AII, increases bradykinin level, and reduces sympathetic nervous system activity. A number of clinical trials have evaluated the possibility that ACE inhibitors may have particular advantages, beyond that of blood pressure control, in reducing cardiovascular and renal outcomes. They decrease proteinuria and retard the rate of progression of renal insufficiency in both diabetic and nondiabetic renal diseases. In most patients with hypertension and heart failure due to systolic and/or diastolic dysfunction, ACE inhibitor is recommended to improve survival.  Experience from clinical trials suggest that drugs that target the renin-angiotensin system (RAS) may have metabolic advantage over drugs such as beta blockers and diuretics.  Epidemiologic studies have established a strong correlation between elevated total cholesterol levels in serum and morbidity and mortality from myocardial infarction. Hyperlipidemia, in particular hypercholesterolemia, is regarded as an independent risk factor in the development of ischemic heart disease.  One study has shown that fosinopril therapy for 6 months resulted in a reduction of microalbuminuria and an improvement in lipid profile and lipoprotein (a) [Lp (a) ] levels in patients with type II diabetes.  In the light of above facts present study had been undertaken with the aim to observe effects of certain ACE inhibitors on serum lipid profile in albino rabbits. The drugs evaluated were Lisinopril and Perindopril.
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