Resistant starch fraction prepared from kintoki bean affects gene expression of genes associated with cholesterol metabolism in rats

Feeding rats beans with resistant starch reduces the serum cholesterol concentration; however, the mechanism is not fully understood. We examined the effects of resistant starch of kintoki (Phaseolus vulgaris, variety) bean on serum cholesterol and hepatic mRNAs in rats. Male F344/Du Crj rats were fed a cholesterol-free diet either with 5 g of cellulose powder (control)/100 g or 5 g of pancreatin-resistant fraction prepared from kintoki bean (kintoki)/100 g diet for 4 weeks. There were no differences in the body weight gain, food intake, liver weight, and mass of cecum contents between the groups. Serum total cholesterol, very low density lipoprotein (VLDL) + intermediate density lipoprotein (IDL) + low density lipoprotein (LDL)-cholesterol, and high density lipoprotein (HDL)-cholesterol levels in the kintoki group were significantly (at least P < 0.05) lower than in the control group throughout the feeding period. There was no difference in the serum triglyceride concentration between two groups throughout the feeding period. Total hepatic cholesterol in the control group was significantly (P < 0.01) lower than in the kintoki groups. Fecal bile acid, cecal acetate, propionate and n-butyrate concentrations in the kintoki group all were significantly (P < 0.05) higher than in the control group. Likewise, hepatic cholesterol 7alpha-hydroxylase, LDL receptor, and SR-B1 mRNA levels in the kintoki group were significantly (P < 0.05) higher than in the control group. The results suggest that resistant starch of kintoki bean reduces serum cholesterol level by increasing hepatic LDL receptor, SR-B1, and cholesterol 7alpha-hydroxylase mRNAs.     

Expression of apolipoprotein A-I mRNA in liver and intestine of cecectomized rats fed beet fiber

Sham-operated and cecectomized rats were fed a cholesterol-free diet with no added fiber (fiber-free) for 10 days, followed by the diet of 15% beet fiber for 10 days. The plasma cholesterol concentrations in rats fed the fiber-free diet were not significantly different between sham-operated and cecectomized groups. Plasma cholesterol concentrations in sham-operated rats were decreased by feeding the beet fiber diet, whereas those in cecectomized rats did not change. Final plasma total cholesterol concentrations in cecectomized rats were significantly higher than in sham-operated rats. This difference was due mainly to lower HDL cholesterol concentrations. The cecectomized rats also tended to have higher apolipoprotein A-I concentrations in plasma. Northern blot analysis revealed that the relative concentrations of ileal apolipoprotein A-I mRNA were the same in the two groups, while hepatic apolipoprotein A-I mRNA levels were significantly higher in cecectomized rats than in sham-operated rats. These data demonstrate that the cecectomy abolished the hepatic apolipoprotein A-I mRNA-lowering effect of dietary beet fiber, and it is suggested that the cecum plays an important role in the regulation of hepatic apolipoprotein A-I expression which seems to be responsible for the hypocholesterolemic effect of dietary beet fiber.     

Effects of dietary fats and cholesterol on liver lipid content and hepatic apolipoprotein A-I, B, and E and LDL receptor mRNA levels in cebus monkeys.

The effects of the long-term administration of the dietary fats coconut oil and corn oil at 31% of calories with or without 0.1% (wt/wt) dietary cholesterol on plasma lipoproteins, apolipoproteins (apo), hepatic lipid content, and hepatic apoA-I, apoB, apoE, and low density lipoprotein (LDL) receptor mRNA abundance were examined in 27 cebus monkeys. Relative to the corn oil-fed animals, no significant differences were noted in any of the parameters of the corn oil plus cholesterol-fed group. In animals fed coconut oil without cholesterol, significantly higher (P less than 0.05) plasma total cholesterol (145%), very low density lipoprotein (VLDL) + LDL (201%) and high density lipoprotein (HDL) (123%) cholesterol, apoA-I (103%), apoB (61%), and liver cholesteryl ester (263%) and triglyceride (325%) levels were noted, with no significant differences in mRNA levels relative to the corn oil only group. In animals fed coconut oil plus cholesterol, all plasma parameters were significantly higher (P less than 0.05), as were hepatic triglyceride (563%) and liver apoA-I (123%) and apoB (87%) mRNA levels relative to the corn oil only group, while hepatic LDL receptor mRNA (-29%) levels were significantly lower (P less than 0.05). Correlation coefficient analyses performed on pooled data demonstrated that liver triglyceride content was positively associated (P less than 0.05) with liver apoA-I and apoB mRNA levels and negatively associated (P less than 0.01) with hepatic LDL receptor mRNA levels. Liver free and esterified cholesterol levels were positively correlated (P less than 0.05) with liver apoE mRNA levels and negatively correlated (P less than 0.025) with liver LDL receptor mRNA levels. Interestingly, while a significant correlation (P less than 0.01) was noted between hepatic apoA-I mRNA abundance and plasma apoA-I levels, no such relationship was observed between liver apoB mRNA and plasma apoB levels, suggesting that the hepatic mRNA of apoA-I, but not that of apoB, is a major determinant of the circulating levels of the respective apolipoprotein. Our data indicate that a diet high in saturated fat and cholesterol may increase the accumulation of triglyceride and cholesterol in the liver, each resulting in the suppression of hepatic LDL receptor mRNA levels. We hypothesize that such elevations in hepatic lipid content differentially alter hepatic apoprotein mRNA levels, with triglyceride increasing hepatic mRNA concentrations for apoA-I and B and cholesterol elevating hepatic apoE mRNA abundance.     

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.     

Studies on the expression of genes encoding apolipoproteins B100 and B48 and the low density lipoprotein receptor in nonhuman primates. Comparison of dietary fat and cholesterol

African green monkeys were fed diets containing low and moderate cholesterol concentrations with either polyunsaturated or unsaturated fat as 40% of calories. Plasma total cholesterol, low density lipoprotein (LDL) cholesterol, and apoB concentrations generally were higher in animals fed (a) the higher dietary cholesterol concentration and (b) saturated fat. At necropsy, liver and intestine were removed, and measurement of mRNAs for LDL receptors (liver) and for apolipoprotein B (liver and intestine) was done. Monkey small intestine mucosa made exclusively apoB48 while the liver made only apoB100, although apoB mRNA in both tissues was the same size (14 kilobases). No dietary cholesterol or fat effects were found for apoB mRNA abundance in the liver, while the animals fed the higher dietary cholesterol level had 50% lower levels of hepatic LDL receptor mRNA. In a separate group of animals, livers were perfused and the rate of apoB secretion was measured. No dietary fat effect on apoB secretion rate was found, and no relationship between plasma LDL cholesterol concentration and the rate of hepatic apoB production existed. These findings support the idea that the dietary factors that increase LDL concentrations act by reducing clearance of apoB-containing particles rather than by increasing production of these lipoproteins. Hepatic LDL receptor mRNA was similar in abundance in polyunsaturated fat and saturated fat-fed animals, suggesting that the difference in plasma cholesterol concentration between these groups is not mediated via effects on LDL receptor mRNA abundance. The level of intestinal apoB mRNA was about 30% higher in animals fed the moderate dietary cholesterol concentration. Earlier studies have shown that more cholesterol is transported in chylomicrons from the intestine when dietary cholesterol levels are higher, and the increased intestinal apoB mRNA abundance may reflect increased intestinal cholesterol transport and chylomicron apoB48 production.     

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.     

In vivo regulation of hepatic LDL receptor mRNA in the baboon. Differential effects of saturated and unsaturated fat

The effects of diets enriched with cholesterol and different fats upon plasma lipoproteins and hepatic low density lipoprotein (LDL) receptor mRNA levels were studied in a group of 18 normal baboons. Animals were fed diets containing 1% cholesterol and 25% fat as either coconut oil, peanut oil, or olive oil for a period of 20 weeks. Plasma total cholesterol, high density lipoprotein (HDL) cholesterol, beta-lipoprotein (LDL + very low density lipoprotein) cholesterol, apolipoprotein B and apolipoprotein A-I were measured in samples obtained at 4-week intervals. All three diet groups demonstrated a statistically significant increase in plasma cholesterol as compared to base line throughout the experiment. Hepatic LDL receptor (LDL-R) mRNA levels were quantified by dot blot hybridization in serial liver biopsies. Animals fed saturated fat sustained a significant reduction in hepatic LDL-R mRNA as compared to those fed either monounsaturated or polyunsaturated fat. A strong negative correlation between LDL-R mRNA and plasma total cholesterol (r = -0.71), HDL cholesterol (r = -0.76), and plasma apo A-I (r = -0.77) was observed only in those animals fed coconut oil. Weak negative correlations between LDL-R mRNA and other plasma parameters did not achieve statistical significance. We conclude that saturated and unsaturated oils may influence plasma cholesterol levels in part through differential effects on LDL receptor biosynthesis in baboons.     

Dietary fat saturation and gender/hormonal status modulate plasma lipids and lipoprotein composition(1)

Male, female and ovariectomized (to mimic menopause) guinea pigs were fed a saturated (SFA) or a polyunsaturated (PUFA) fat diet for 4 weeks to determine the effects of dietary fat saturation on lipoprotein levels and composition and to assess whether gender and hormonal status modulate the cholesterolemic response. Both diets contained 15g/100 g fat and 0.04 g/100 g cholesterol and were identical in composition except for the type of fat. The SFA diet contained 50% saturated fat (25% lauric + myristic fatty acids), 25% PUFA and 25% monounsaturated fatty acids while the PUFA diet had 50% PUFA (linoleic acid), 25% monounsaturated and 25% SFA fatty acids. Plasma LDL cholesterol (LDL-C) was an average 21% lower in guinea pigs fed PUFA compared to those fed SFA (P < 0.05). In addition, ovariectomized guinea pigs, both in the SFA and PUFA groups, had 20–33% higher LDL-C than either males or females (P < 0.01). VLDL cholesterol was 70% higher in the PUFA-fed animals (P < 0.0001). A gender effect was observed in plasma HDL cholesterol (HDL-C) with females and ovariectomized guinea pigs having 30–42% higher HDL-C than males (P < 0.01). LDL susceptibility to oxidation was not affected by dietary fat saturation or gender. In contrast, VLDL and LDL composition were significantly influenced by diet and gender. VLDL particles were larger in size in guinea pigs fed the SFA diets (P < 0.01) while LDL particles were larger in female guinea pigs (P < 0.001). Hepatic lipids were influenced by the interaction between diet and group. Hepatic cholesterol (P < 0.01) and TAG concentrations (P < 0.0001) were highest in female guinea pigs fed the PUFA diet. Since the liver is the major site of lipoprotein synthesis and catabolism, these results suggest that not only diet but also gender may play a major role in determining the composition and size of lipoproteins.     

Effect of pectin and amidated pectin on cholesterol homeostasis and cecal metabolism in rats fed a high-cholesterol diet

Two experiments were performed to compare the effect of pectin and its hydrophobic derivatives on homeostasis of cholesterol and cecal metabolism in male young rats. Control rats were fed a diet supplemented with palm fat and cholesterol (50 and 10 g/kg, respectively). Rats of other groups were fed the same diet containing citrus pectin or octadecylpectinamide (60 g/kg). Diets were fed for 4 weeks. In experiment I, pectinamide of lower degree of amidation (30 %) increased serum HDL cholesterol from 1.20 to 1.43 micromol/ml (p>0.05) at the expense of other cholesterol fractions. In experiment II, pectinamide of a higher degree of amidation (53 %) significantly decreased total serum cholesterol from 2.08 to 1.67 micromol/ml. Amidated pectins at both levels of substitution significantly decreased hepatic concentrations of cholesterol and fat. In both experiments the relative weight of cecum in the pectinamide group was significantly lower than in pectin group. The highest cecal concentrations of short-chain fatty acids (SCFA) were found in rats fed a diet with pectin (133.2 and 129.3 micromol/g in experiment I and II, respectively). In other groups, cecal SCFA was significantly (pectinamide groups) or non-significantly (controls) lower. In wet feces, SCFA concentrations were higher and butyrate molar proportions lower than in corresponding cecal contents. Pectinamide of a lower or higher degree of substitution significantly increased fecal content of cholesterol from 18.5 and 17.3 micromol/g in controls to 31.8 and 28.0 micromol/g, respectively. Corresponding concentrations of coprostanol were decreased. Effects of pectin on cholesterol homeostasis were absent or marginal. Histological examination revealed that hepatic tissue of control and pectin-fed rats was infiltrated with lipids. The Sudan black-positive material was absent in the liver of rats fed pectinamides. No pathological changes of liver tissue were apparent. In summary, hydrophobic amidated pectins significantly altered cholesterol homeostasis in rats and might be considered as a clinically effective hypocholesterolemic agent. Low cecal SCFA concentrations in rats fed pectinamides suggest that amidation of pectin had decreased its fermentability.     

Pectin and psyllium decrease the susceptibility of LDL to oxidation in guinea pigs

These studies were undertaken to determine whether pectin (PE) and psyllium (PSY) intake affect the circulating levels of alpha-tocopherol and the susceptibility of low density lipoprotein (LDL) to oxidation. For that purpose, male Hartley guinea pigs were fed 19 g/100 g of a fat mix with a 2:1:1 ratio of saturated:polyunsaturated:monounsaturated fatty acids and 35 g/100 g total carbohydrate with 80% of the carbohydrate energy contributed by sucrose. Diets were identical in composition except for the fiber source: cellulose (control diet), PE, or PSY. Guinea pigs fed PE or PSY had 36% and 67% lower plasma cholesterol concentrations, respectively, compared with controls (P < 0.001). This plasma cholesterol lowering was associated with both very low density lipoproteins and LDL cholesterol fractions. Intake of PE or PSY resulted in 54% lower plasma triacylglycerol (TAG) concentrations compared with the control group (P < 0.001). LDL from PE and PSY fed guinea pigs contained fewer molecules of cholesteryl ester, and alpha-tocopherol concentrations in this particle were 49% and 66% higher, respectively, compared with controls. In addition, LDL from guinea pigs fed soluble fiber exhibited less susceptibility to oxidation than those from the control group, as determined by thiobarbituric acid-reactive substances formation. Hepatic free and esterified cholesterol were 32% lower and hepatic TAG was 25% lower in guinea pigs fed PE and PSY compared with controls. The data from these studies confirm that PE and PSY reverse the hyperlipidemia associated with high fat-sucrose diets and demonstrate a potential antioxidant effect of soluble fiber on circulating LDL.     

Corn husk oil lowers plasma LDL cholesterol concentrations by decreasing cholesterol absorption and altering hepatic cholesterol metabolism in guinea pigs

To test the hypocholesterolemic mechanisms of corn husk oil (CoHO), male Hartley guinea pigs were fed diets containing increasing doses of CoHO, either 0 (control), 5, 10, or 15 g/100 g, and 0.25 g/100 g cholesterol. A positive control group (LC) with low dietary cholesterol (0.04 g/100 g) was also included. Fat was adjusted to 15 g/100 g in all diets by the addition of regular corn oil. Plasma low density lipoprotein (LDL) cholesterol concentrations were 32, 55, and 57% (P < 0.0005) lower with increasing doses of CoHO. In addition, intake of CoHO resulted in 32 to 43% lower hepatic total and esterified cholesterol and 55 to 60% lower triacylglycerol concentrations compared with the control group (P < 0.01). CoHO intake resulted in plasma and hepatic cholesterol concentrations similar to those in guinea pigs from the LC group. The number of cholesteryl ester and free cholesterol molecules was higher in LDL from the control group than in LDL from the CoHO or the LC groups. Hepatic beta-hydroxy-beta-methylglutaryl-coenzyme A reductase activity was not modified by CoHO intake whereas cholesterol 7alpha-hydroxylase was up-regulated by 45 to 49% (P < 0.01) in the 10 and 15 g/100 g CoHO groups. Hepatic acyl coenzyme A cholesterol acyltransferase activity was down-regulated in a dose-dependent manner by 54, 58, and 63% with increasing doses of CoHO. CoHO intake resulted in increased fecal cholesterol excretion by 40 to 55% compared with the control and LC groups. Total fecal neutral sterol excretion was enhanced 42 to 55% by CoHO compared with the control group and by 59 to 68% compared with the LC group. The data from these studies suggest that CoHO has its hypocholesterolemic effect by decreasing cholesterol absorption and increasing bile acid output. These alterations in the intestinal lumen alter hepatic cholesterol metabolism and may affect the synthesis and catabolism of lipoproteins.     

Exercise improves plasma lipid profiles and modifies lipoprotein composition in guinea pigs

These studies were conducted to determine the effects of exercise training on plasma lipoprotein levels and metabolism in the guinea pig to evaluate potential utilization of this model for studies of exercise-mediated effects on the regulation of sterol and lipoprotein metabolism and atherosclerosis regression. Male guinea pigs (n = 5 per group) were randomly assigned to either a control or an exercise group. The exercise protocol consisted of a 7-week training program, 5 days/wk on a rodent treadmill. Final speed and duration were 33 meters/min for 30–40 min per session. Guinea pigs in the exercise group had 33% lower plasma triacylglycerol concentrations (P < 0.01), 66% higher HDL cholesterol levels (P < 0.05) and 31% lower plasma free fatty acids (P < 0.05) than guinea pigs from the non-exercised group. In addition, lipoprotein lipase activity in the heart was 50% higher (P < 0.025) in guinea pigs allocated to the exercise protocol. Exercise training resulted in modifications in composition and size of lipoproteins. The concentrations of free cholesterol in LDL and HDL were higher in the exercised guinea pigs. The LDL peak density values were lower in guinea pigs from the exercise group compared to controls suggesting that exercise training resulted in larger LDL particles. In contrast, no significant effects due to exercise were observed in hepatic cholesterol concentrations, hepatic HMG-CoA reductase activity or LDL binding to guinea pig hepatic membranes. These data indicate that exercise had a more pronounced effect on the intravascular processing of lipoproteins than on hepatic cholesterol metabolism. In addition, the pattern of changes in guinea pig lipoprotein metabolism, in response to exercise training, was similar to reported effects in humans.     

Undaria pinnatifida soluble fiber regulates Angptl3-LPL pathway to lessen hyperlipidemia in mice

Angiopoietin-like protein 3 (Angptl3)–lipoprotein lipase (LPL) pathway may be a useful pharmacologic target for hyperlipidemia. The present study was conducted to test the effect of soluble fiber extracted from Undaria pinnatifida (UP), on hyperlipidemia in apolipoprotein E-deficient (ApoE^?/?) mice. Forty mice were divided into four groups (n?=?10): control group (C57BL/6J mice), ApoE^?/? mice group, and two groups of ApoE^?/? mice treated with UP fiber (5 or 10 % per day). UP soluble fiber treatment significantly decreased plasma and hepatic total cholesterol, triglycerides levels, plasma low-density lipoprotein cholesterol, and malondialdehyde concentrations and increased plasma high-density lipoprotein cholesterol level and downregulated protein expression of Angptl3 concomitantly with upregulated protein expression of LPL. In addition, T0901317 caused elevated expression of hepatic Angptl3 protein, and the effect of T0901317 was also abrogated by UP soluble fiber in C57BL/6J mice. The present results suggest that the UP soluble fiber regulates Angptl3-LPL pathway to lessen hyperlipidemia in mice.     

Superiority of dietary safflower oil over olive oil in lowering serum cholesterol and increasing hepatic mRnas for the LDL receptor and cholesterol 7alpha-hydroxylase in exogenously hypercholesterolemic (exHC) rats

The exogenously hypercholesterolemic (ExHC) rat is a strain segregated from SD rats with a high response to dietary cholesterol. To understand the underlying mechanism(s) for this hypercholesterolemia, the interactive effects of dietary fatty acid and the susceptibility of rats to dietary cholesterol on the serum cholesterol concentration and hepatic mRNA abundance of the low-density lipoprotein (LDL) receptor, cholesterol 7alpha-hydroxylase (7alpha-hydroxylase) and 3-hydroxyl-3methylglutaryl (HMG) CoA reductase were examined. Both strains were fed on a diet supplemented with 10% each of olive, safflower or coconut oil with or without the addition of 1% cholesterol for one week. The ExHC rats fed on olive, safflower and coconut oil in combination with cholesterol respectively resulted in a 3.5-, 2.0- and 2.1-fold higher serum cholesterol concentration than that in the animals fed on the corresponding dietary fats without any supplementation of cholesterol (p < 0.01 by dietary cholesterol or type of fat). The dietary cholesterol dependent-elevation of serum cholesterol in the SD rats was less than 1.5-fold (p<0.01) and there was no dietary fat effect. The ExHC rats fed on the safflower oil-containing diet supplemented with cholesterol resulted in a higher mRNA abundance of the LDL receptor and 7alpha-hydroxylase than in the corresponding fat-fed rats without cholesterol (p<0.05). There was no dietary cholesterol-dependent change of mRNA abundance in either strain fed on olive or coconut oil, except for a decreased abundance of HMG CoA reductase mRNA in the olive oil-fed ExHC rats and coconut oil-fed Sprague-Dawley (SD) rats (p<0.05). These results indicate that the hepatic mRNA abundance of the LDL receptor and of 7alpha-hydroxylase depended on the dietary combination of cholesterol and a fatty acid and suggest that a linoleic acid-rich diet may alleviate exogenous hypercholesterolemia by activating the process involved in the hepatic uptake and biliary excretion of serum cholesterol.     

Leptin induces the hepatic high density lipoprotein receptor scavenger receptor B type I (SR-BI) but not cholesterol 7alpha-hydroxylase (Cyp7a1) in leptin-deficient (ob/ob) mice

Cholesterol elimination from the body involves reverse cholesterol transport from peripheral tissues in which the elimination of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol by the liver and subsequent biliary excretion as free cholesterol and bile acids are important. In situations of peripheral fat and cholesterol accumulation, such as obesity, these pathways may be overloaded, contributing to increased cholesterol deposition. Leptin has an important role in obesity, suppressing food intake and increasing energy expenditure. This hormone, which is absent in genetically obese ob/ob mice, is also thought to be involved in the coordination of lipid excretion pathways, although available data are somewhat inconsistent. We therefore studied the expression of the hepatic HDL receptor, scavenger receptor class B type I (SR-BI), and the LDL receptor as well as the rate-limiting enzyme in bile acid synthesis, cholesterol 7alpha-hydroxylase (Cyp7a1), in leptin-deficient ob/ob mice and their wild-type controls. In ob/ob mice, protein levels of both LDL receptor and SR-BI were reduced, whereas LDL receptor mRNA levels were increased and those of SR-BI were reduced, regardless of challenge with a 2% cholesterol diet. In ob/ob mice, the enzymatic activity and mRNA for Cyp7a1 were reduced, and the increase in response to dietary cholesterol was blunted. Upon short-term (2 days) treatment with leptin, a dose-dependent increase was seen in the SR-BI protein and mRNA, whereas the Cyp7a1 protein and mRNA were reduced. Our findings indicate that leptin is an important regulator of hepatic SR-BI expression and, thus, HDL cholesterol levels, whereas it does not stimulate Cyp7a1 and bile acid synthesis.     

Glucose tolerance, plasma lipoproteins and tissue lipoprotein lipase activities in body builders

Oral glucose tolerance, insulin binding to erythrocyte receptors, serum lipids, and lipoproteins, and lipoprotein lipase activities of adipose tissue and skeletal muscle were measured in nine body builders (relative body weight (RBW) 118 +/- 4%), eight weight-matched (RBW 120 +/- 5%) and seven normal-weight controls (RBW 111 +/- 3%). The body builders had 50% higher relative muscle mass of body weight (% muscle) and 50% smaller relative body fat content (% fat) than the two other groups (P less than 0.005). Maximal aerobic power was comparable in the three groups. In the oral glucose tolerance test (OGTT), blood glucose levels, and plasma insulin levels were lower (P less than 0.05) in the body builders than in weight-matched controls. Insulin binding to erythrocytes was similar in each group. On the basis of multiple linear regression analysis, 87% of the variation in plasma insulin response could be explained by body composition (% muscle and % fat) and VO2max. Plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, and very low-density lipoprotein (VLDL) triglyceride concentrations were significantly lower in the body builders than in weight-matched controls. In comparison with the normal-weight group, the body builders had a lower total cholesterol level. High density lipoprotein (HDL) cholesterol, its subfractions (HDL2 and HDL3 cholesterol) and lipoprotein lipase (LPL) activities of adipose tissue and skeletal muscle were comparable in all three groups. Partial correlation analysis showed a positive relationship between plasma total triglyceride, total cholesterol and LDL cholesterol on the other hand and the % fat on the other.(ABSTRACT TRUNCATED AT 250 WORDS)     

The peroxisome proliferator-activated receptor alpha (PPARalpha) agonist ciprofibrate inhibits apolipoprotein B mRNA editing in low density lipoprotein receptor-deficient mice: effects on plasma lipoproteins and the development of atherosclerotic lesions

Low density lipoprotein receptor (LDLR)-deficient mice fed a chow diet have a mild hypercholesterolemia caused by the abnormal accumulation in the plasma of apolipoprotein B (apoB)-100- and apoB-48-carrying intermediate density lipoproteins (IDL) and low density lipoproteins (LDL). Treatment of LDLR-deficient mice with ciprofibrate caused a marked decrease in plasma apoB-48-carrying IDL and LDL but at the same time caused a large accumulation of triglyceride-depleted apoB-100-carrying IDL and LDL, resulting in a significant increase in plasma cholesterol levels. These plasma lipoprotein changes were associated with an increase in the hepatic secretion of apoB-100-carrying very low density lipoproteins (VLDL) and a decrease in the secretion of apoB-48-carrying VLDL, accompanied by a significant decrease in hepatic apoB mRNA editing. Hepatic apobec-1 complementation factor mRNA and protein abundance were significantly decreased, whereas apobec-1 mRNA and protein abundance remained unchanged. No changes in apoB mRNA editing occurred in the intestine of the treated animals. After 150 days of treatment with ciprofibrate, consistent with the increased plasma accumulation of apoB-100-carrying IDL and LDL, the LDLR-deficient mice displayed severe atherosclerotic lesions in the aorta. These findings demonstrate that ciprofibrate treatment decreases hepatic apoB mRNA editing and alters the pattern of hepatic lipoprotein secretion toward apoB-100-associated VLDL, changes that in turn lead to increased atherosclerosis.     

Dietary oxidized cholesterol decreases expression of hepatic microsomal triglyceride transfer protein in rats

The aim of this study was to compare the effects of dietary oxidized cholesterol and pure cholesterol on plasma and very low density lipoprotein (VLDL) lipids and on some parameters of VLDL assembly and secretion in rats fed two different dietary fats. Four groups of male growing Sprague-Dawley rats were fed diets containing pure or oxidized cholesterol (5 g/kg diet) with either coconut oil or salmon oil as dietary fat (100 g/kg diet) for 35 days. Rats fed oxidized cholesterol supplemented diets had significantly lower concentrations of triglycerides and cholesterol in plasma and VLDL than rats fed pure cholesterol supplemented diets irrespective of the type of fat. In addition, rats fed oxidized cholesterol supplemented diets had significantly lower relative concentrations of microsomal triglyceride transfer protein messenger ribonucleic acid (mRNA) than rats fed pure cholesterol supplemented diets. In contrast, hepatic lipid concentrations and the relative concentration of apolipoprotein B mRNA were not influenced by the dietary factors investigated. Parameters of hepatic lipogenesis (relative mRNA concentration of sterol regulatory element binding protein-1c and activity of glucose-6-phosphat dehydrogenase) were significantly reduced by feeding fish oil compared to coconut oil, but were not affected by the type of cholesterol. In conclusion, the data of this study suggest, that dietary oxidized cholesterol affects VLDL assembly and/or secretion by reducing the synthesis of MTP but not by impairing hepatic lipogenesis or synthesis of apolipoprotein B.     

Naringin alters the cholesterol biosynthesis and antioxidant enzyme activities in LDL receptor-knockout mice under cholesterol fed condition

The purpose of the current study was to evaluate the lipid lowering and antioxidant capacity of naringin in LDL receptor knockout (LDLR-KO) mice fed a cholesterol (0.1 g/100 g) diet. As such, naringin or lovastatin (0.02 g/100 g) was supplemented in a cholesterol diet for 6 weeks. The naringin and lovastatin supplementation significantly lowered the plasma total cholesterol level compared to the control group. The plasma and hepatic triglyceride level was only lowered by the lovastatin supplement, while the hepatic cholesterol content was lowered by both the naringin and lovastatin supplements compared to the control group. The hepatic HMG-CoA reductase activity was significantly lower in the naringin and lovastatin supplemented groups than in the control group, whereas the ACAT activity was unaffected. The excretion of total sterol was significantly higher in the naringin and lovastatin groups compared to the control group due to significant changes in the acidic and neutral sterol, respectively. When comparing the hepatic antioxidant enzyme activities, the superoxide dismutase, catalase, and glutathione reductase activities were all significantly higher in the naringin-supplemented group than in the control group, while only the lovastatin supplement increased the glutathione reductase activity. Accordingly, the current results confirmed that naringin lowers the plasma cholesterol level via the inhibition of hepatic HMG-CoA reductase activity and increases the excretion of fecal sterol. Naringin was also found to improve the activities of hepatic antioxidant enzymes against oxidative stress in a hypercholesterolemic animal model, i.e. cholesterol-fed LDLR-KO mice.     

兔主动脉平滑肌细胞低密度脂蛋白受体相关蛋白(LRP)的诱导表达调节

在兔主动脉平滑肌细胞 ( SMC)培养基中分别加入正常低密度脂蛋白 ( N- LDL)、氧化低密度脂蛋白 ( ox- LDL)、正常极低密度脂蛋白 ( N- VLDL)、氧化极低密度脂蛋白 ( ox- VLDL)和 β-极低密度脂蛋白 (β- VLDL )培养 2 4 h后 ,用定量 RT- PCR和配体结合实验检测平滑肌细胞 LRP的m RNA和蛋白质水平的表达 .结果表明 :五种脂蛋白均能在转录和翻译水平诱导兔主动脉平滑肌细胞的 LRP表达 ,尤以富含胆固醇的 N- LDL ,ox- LDL和β- VLDL的刺激作用更明显 .用胆固醇单独或与脂蛋白共同温育 SMC后 ,发现胆固醇本身可促进 SMC的 LRP蛋白水平的表达 ,脂蛋白与胆固醇的共同刺激作用更为显著 .结果提示 :上述五种脂蛋白对 SMC上 LRP的表达有上调作用 ,其机制可能主要是通过其中的胆固醇来实现的 .