The hypochylomicronemic effect of beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) is mediated by a decrease in apolipoprotein C-III

Treatment of rats fed a balanced Purina Chow diet with beta,beta'-tetramethyl-substituted hexadecanedioic acid (MEDICA 16) (Bar-Tana, J., Rose-Kahn, G., and Srebnik, M. (1985) J. Biol. Chem. 260, 8404-8410) resulted in an acute 70-80% decrease in plasma chylomicrons-triacylglycerols which was sustained as long as the drug was administered. The hypochylomicronemic effect resulted from an enhanced plasma clearance of chylomicrons whereas their intestinal production and absorption remained unaffected. Chylomicrons-triacylglycerols clearance in MEDICA 16-treated rats was characterized by a fast initial phase lasting for 1-2 min and consisting of elimination of 50-60% of the injected chylomicrons' tracer at a fractional clearance rate of 0.77 +/- 0.27 min-1 as compared to 0.08 +/- 0.01 min-1 in nontreated rats. The fractional clearance rate of chylomicrons-cholesterol ester was similarly affected by MEDICA 16 treatment and amounted to 0.48 +/- 0.05 and 0.05 +/- 0.01 min-1 in MEDICA 16-treated and nontreated rats, respectively. The increased fractional clearance rate of plasma chylomicrons in MEDICA 16-treated rats presumably reflects the primary action of the drug rather than being secondary to the hypochylomicronemic state, since it was similarly observed in MEDICA 16-treated animals made transiently normolipemic by loading them with intestinal lipid. The increase in the fractional clearance rate of plasma chylomicrons resulted from their enhanced uptake by the liver complemented with their activated extrahepatic catabolism. The activation of both catabolic modes in MEDICA 16-treated rats could be accounted for by a 10-fold decrease in the apoC-III content of plasma chylomicrons. No increase was observed in hepatic apoB,E or apoE receptors, nor in the maximal capacity of lipoprotein lipase. The pharmacological reduction of plasma apoC-III may thus offer a treatment mode of choice for selected hyperlipidemic states.     

Inhibition of lipid synthesis by beta beta'-tetramethyl-substituted, C14-C22, alpha, omega-dicarboxylic acids in cultured rat hepatocytes

beta beta'-Methyl-substituted, C14-C18, alpha, omega-dicarboxylic acids (MEDICA 14-18) were found to inhibit fatty acids and cholesterol synthesis in cultured rat hepatocytes. Maximum inhibition was observed with MEDICA 16, amounting to a 50% decrease in 3H2O and acetate incorporation into fatty acids and cholesterol in the presence of 0.08 mM of the drug added to the culture medium. Inhibition of lipogenesis was not accompanied by inhibition of palmitate or glycerol esterification into neutral lipids and phospholipids. The respective capacities of MEDICA homologues of varying acyl chain length as inhibitors of fatty acid and cholesterol synthesis in cultured rat hepatocytes and in vivo (Bar-Tana, J., Rose-Kahn, G., and Srebnik, M. (1985) J. Biol. Chem. 260, 8404-8410) correlated well with their respective inhibitory effect on liver ATP-citrate lyase. Thus, MEDICA 16 inhibited liver ATP-citrate lyase competitively to citrate with a Ki of 16 microM as compared to a Km of 0.8 mM for the citrate substrate.     

Hypolipidemic effect of beta, beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) in normal and nephrotic rats

Treatment of normal or puromycin aminonucleoside-nephrotic rats, kept on a balanced Purina chow diet, with beta, beta'-tetramethyl-substituted hexadecanedioic acid (MEDICA 16) (Bar-Tana, J., G. Rose-Kahn, and M. Srebnik. 1985. J. Biol. Chem. 260: 8404-8410) resulted in an acute reversible inhibition of liver lipogenesis and cholesterogenesis with a concomitant hypolipidemic effect which was sustained as long as the drug was administered. The hypolipidemic effect in normal and nephrotic rats consisted of 70-80% and 40-60% reduction in plasma VLDL-triacylglycerols and cholesterol, respectively, with a respective increase in the HDL-cholesterol/(VLDL + LDL)-cholesterol ratio. The observed hypolipidemic effect was accompanied by a 10-fold decrease in VLDL-apoC-III content with a concomitant enrichment of the VLDL fraction by VLDL remnants having an increased apoB-100/apoB-48 ratio. The pharmacological reduction of VLDL by MEDICA 16 may offer a treatment mode of choice for selected hyperlipidemic states.     

Inhibition of rat liver acetyl-CoA carboxylase by beta, beta'-tetramethyl-substituted hexadecanedioic acid (MEDICA 16)

Rat liver acetyl-CoA carboxylase activity was inhibited by the free as well as the CoA monothioester of beta, beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) (Bar-Tana, J., Rose-Kahn, G. and Srebnik, M. (1985) J. Biol. Chem. 260, 8404-8410 (1985). (1) The CoA monothioester of MEDICA 16 served as a dead-end inhibitor with an apparent Ki of 2 microM and 58 microM for the biotin-carboxylated and noncarboxylated enzyme forms, respectively. MEDICA 16-CoA binding was not mutually exclusive with that of citrate and did not affect the avidin-resistance of rat liver acetyl-CoA carboxylase. (2) The free dioic acid of MEDICA 16 was competitive to citrate, having an apparent Ki of about 70 microM, as compared to a Ka of 2-8 mM for the citrate activator. Inhibition of the carboxylase by the free dioic acid of MEDICA 16 was accompanied by an increase in its avidin resistance. The resultant inhibition of acetyl-CoA carboxylase by MEDICA 16 and its CoA thioester, together with the previously reported citrate-competitive inhibition of ATP-citrate lyase by MEDICA 16, may account for the observed hypolipidemic effect of MEDICA 16 under dietary conditions where liver lipogenesis constitutes a major flux of liver lipid synthesis.     

Effects of phenotype, sex, and diet on plasma lipids in LA/N-cp rats

The LA/N-corpulent (cp) rat is a recently developed congenic strain which exhibits obesity. The effects of phenotype and sex on serum and lipoprotein lipid content were examined in LA/N-cp rats fed either a control or an atherogenic diet high in saturated fat and protein. Obese rats were pair-fed to equivalent lean animals. Results from this study indicate that sex, phenotype, and diet exert significant effects on plasma and lipoprotein cholesterol content. Plasma cholesterol levels were higher in obese compared with lean rats, females than in males, and rats consuming the atherogenic diet compared with the control diet. Plasma and lipoprotein triglyceride levels were significantly increased only in obese compared with lean animals. The increased plasma cholesterol and triglyceride was observed primarily in the chylomicron and very low density lipoprotein fractions. Increased levels of plasma cholesterol were not a result of increased dietary cholesterol absorption or increased liver cholesterol biosynthesis. These data suggest that LA/N-cp rats can serve as a unique rodent model for the study of the interrelationships between hyperlipidemia, obesity, and coronary heart disease.     

Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin: cholesterol acyltransferase in cynomolgus monkeys

The effects of intravenous injection of lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF) were investigated in cynomolgus monkeys (Macaca fascicularis). Injection of 20 micrograms/kg of LPS from E. coli (serotype 055:B5) into cynomolgus monkeys fed a monkey chow diet caused a twofold increase in plasma triglyceride and a 25% reduction in plasma cholesterol 48 h after injection. Similar results were found with injection of recombinant human TNF at a dose of 20 micrograms/kg into chow-fed animals. However, injection of the same dose of LPS or TNF into animals fed an atherogenic diet containing saturated fat and cholesterol resulted in a 2.4- to 5-fold increase in plasma triglyceride concentrations and no significant change in plasma cholesterol levels. The fall in plasma cholesterol levels observed in chow-fed animals was associated with a 57% decrease in the cholesteryl ester (CE) content in low density lipoprotein (LDL) and 35% decrease in CE in high density lipoprotein (HDL) in LPS-injected animals, and a decrease of 33% in CE concentration of LDL and 41% in CE of HDL in animals injected with TNF. In animals fed the atherogenic diet containing saturated fat and cholesterol, the injection of both LPS and TNF also resulted in a significant decrease in the CE content of LDL and HDL. However, the plasma total cholesterol levels did not change in the animals fed saturated fat and cholesterol because the decrease in CE content of LDL and HDL was offset by an increase in very low density lipoprotein (VLDL)-CE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive effect of diet compared with drug treatment in obese men with mild hypertension.

OBJECTIVE--To determine whether dietary treatment has a similar antihypertensive effect to conventional drug treatment while being superior to drugs in improving serum lipid concentrations in obese men with mild hypertension. DESIGN--Six week run in period followed by randomisation to either diet or drug treatment groups for one year. SETTING--Outpatient clinic in city hospital. PATIENTS--61 Men aged 40-69 years, body mass index greater than or equal to 26, diastolic blood pressure 90-104 mm Hg when untreated. Exclusion criteria were signs of organ damage secondary to hypertension and diseases that might have interfered with compliance or with interpretation of results. INTERVENTIONS--Dietary treatment was based on weight reduction, restriction of sodium, and decrease of excess alcohol intake (defined as greater than or equal to 250 g alcohol per week). Drug treatment used a stepped care approach with atenolol as drug of first choice. MAIN OUTCOME MEASURES--Diastolic blood pressure less than 90 mm Hg; absolute reductions in blood pressure and serum lipid concentrations. RESULTS--Mean body weight decreased 7.6 kg in the diet group and increased 0.9 kg in the drug treatment group (p less than 0.0001), and mean sodium excretion decreased 42 and 10 mmol/24 h respectively (p = 0.019). There was no difference in reported alcohol intake. Mean systolic blood pressure decreased 4 mm Hg in the diet group and 16 mm Hg in the drug group (p = 0.003) and diastolic blood pressure 3 and 11 mm Hg respectively (p = 0.002). Diastolic blood pressure of 90 mm Hg was attained by 29% of the diet group (nine men) and 73% (22) of those receiving drug treatment (mean difference 44%, 95% confidence interval 21 to 67%, p = 0.001). Dietary treatment produced decreases in mean serum concentrations of total and low density lipoprotein cholesterol as well as triglycerides and an increase in high density lipoprotein cholesterol concentration. In the drug treatment group the changes were in the opposite direction, and the groups differed significantly in all but total cholesterol. CONCLUSIONS--Dietary treatment was inferior to conventional drug treatment in controlling mild hypertension but superior in lowering serum concentrations of lipids.     

Dietary ganglioside decreases cholesterol content, caveolin expression and inflammatory mediators in rat intestinal microdomains

Membrane microdomains rich in cholesterol and sphingolipids, including gangliosides (GGs), are known to be important regions for cell signaling and binding sites for various pathogens. Cholesterol depletion inhibits the cellular entry of pathogens and also reduces inflammatory signals by disrupting microdomain structure. Our previous study showed that dietary gangliosides increased total ganglioside incorporation while decreasing cholesterol in the intestinal mucosa. We hypothesized that diet-induced reduction in cholesterol content in the intestinal mucosa disrupts microdomain structure resulting in reduced pro-inflammatory signals. Male weanling Sprague-Dawley rats were fed semipurified diets for 2 weeks. Experimental diets were formulated to include either ganglioside-enriched lipid (GG diet, 0.02% gangliosides [w/w of diet] ) or polyunsaturated fatty acid (PUFA diet, 1% arachidonic acid and 0.5% docosahexaenoic acid, w/w of total fat), in a control diet containing 20% fat. Levels of cholesterol, GG, caveolin, platelet activating factor (PAF), and diglyceride (DG) were measured in the microdomain isolated from the intestinal brush border. The GG diet increased total gangliosides by 50% with a relative increase in GD3 and a relative decrease in GM3. Cholesterol content was also reduced by 23% in the intestinal microdomain. These changes resulted in a significant decrease in the ratio of cholesterol to ganglioside. The GG diet and the PUFA diet were both associated with reduction in caveolin, PAF, and DG content in microdomains, whereas no change occurred in the ganglioside profile of animals fed the PUFA diet. Dietary gangliosides decrease the cholesterol/ganglioside ratio, caveolin, PAF and DG content in microdomains thus exerting a potential anti-inflammatory effect during gut development.     

Long-term hypolipaemic effect of apple pulp on golden hamsters with alimentary hyperlipoproteinaemia

Golden hamsters with alimentary hyperlipoproteinaemia (fed on a diet in which 44% of the energy was accounted for by fats, 52 mg cholesterol (CH)/100 g) were given apple pulp (10% of the diet) for six months. From the end of the first month up to the end of the experiment, elevation of serum CH, triacylglycerol (TG) and phospholipid (PL) levels and CH and TG accumulation in the liver were effectively inhibited. At the close of the experiment, hyperlipoproteinaemia was characterized by an increase in the amount of very low density lipoproteins (VLDL), which carried 60-80% of all circulating lipids, accounted for over 70% of the total lipoprotein pool and transported almost 60% of the serum CH (high density lipoproteins--HDL--only 16%). The apple diet markedly reduced (by 50-80%) the amount of all lipids in the lipoproteins within density limits of 1,006-1,063 kg/m3 and lowered the total lipid concentration in these density classes and in the lipoprotein pool as a whole (by 50%). The proportion of the individual lipoprotein classes in the lipoprotein pool was not significantly affected. The apple diet did not affect either the chemical composition of HDL or their participation in the lipoprotein pool, but raised the proportion of serum CH transported in this lipoprotein class. Neither the lipoprotein lipase activity of the adipose tissue nor lecithin:cholesterol acyltransferase activity were influenced by the apple diet.     

3-Hydroxy-3-methylglutaric acid (HMGA) reduces dietary cholesterol induction of saturated bile in hamster

3-Hydroxy-3-methylglutaric acid (HMGA) is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoAR) and strongly reduces cholesterol biosynthesis both in vitro and in vivo. Since the effects of this compound on biliary lipid composition are hitherto unknown, we have investigated whether it prevents dietary cholesterol induction of saturated bile in the hamster. Female Golden Syrian hamsters have been divided into four groups and treated for 10 weeks as follows: I) Standard diet, containing 0.8 mg cholesterol/g food; II) Standard diet plus HMGA (100 mg/kg b.w./day per os); III) Lithogenic diet containing 2.4 mg cholesterol/g food; IV) Lithogenic diet plus HMGA as above. The results indicate that HMGA is effective in reducing both bile cholesterol supersaturation and hypercholesterolemia. Inhibition of hepatic cholesterogenesis at the level of mevalonate synthesis by HMGCoAR and reduction of intestinal cholesterol absorption may be responsible for these effects.     

The influence of dietary vitamin E, fat, and methionine on blood cholesterol profile, homocysteine levels, and oxidizability of low density lipoprotein in the gerbil

A 90-day feeding study with gerbils was conducted to evaluate the influence of dietary vitamin E levels (25 mg/kg diet, 75 mg/kg, 300 mg/kg, and 900 mg/kg), two levels of dietary methionione (casein or casein+L-methionine (1% w/w)) and two sources of lipid (soybean oil [20%] or soybean oil [4%]+coconut oil [16%, 1:4 w/w]) upon serum lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol). In addition, this study examined the effects of diet-induced hyperhomocysteinemia and supplemental dietary vitamin E on the oxidation of low density lipoproteins. Tissue vitamin E (heart, liver, and plasma) demonstrated a dose response (P≤0.001) following the supplementation with increasing dietary vitamin E (25, 75, 300, and 900 mg/kg). In addition, tissue vitamin E levels were found to be higher (P≤0.001) in those animals receiving a combination of coconut oil+soybean oil as compared to the group receiving soybean oil solely. Blood cholesterol profiles indicated an increase (P≤0.001) in total cholesterol and LDL cholesterol by the influence of saturated fat and supplemental methionine. Low-density lipoprotein cholesterol profile demonstrated a reduction (P≤0.001) at the higher dietary vitamin E levels (300 and 900 mg/kg) as compared to the 25 mg/kg and 75 mg/kg dietary vitamin E. Plasma protein carbonyls were not influenced by dietary vitamin E nor by supplemental methionine intake. In vitro oxidation of LDL showed that vitamin E delayed the lag time of the oxidation phase (P≤0.001) and reduced total diene production (P≤0.001). On the contrary, supplemental methionine decreased (P≤0.001) the delay time of the lag phase, whereas total diene production was increased (P≤0.001). Plasma lipid hydroperoxides were significantly reduced (P≤0.05) with supplemental dietary vitamin E, whereas supplemental L-methionine (1%) resulted in a significant (P≤0.05) increase in lipid plasma hydroperoxide formation. Plasma homocysteine was elevated (P≤0.001) with supplemental dietary L-methionine (1%) as well as the inclusion of dietary saturated fat. The present data showed that 1) a combination of dietary lipids (saturated and unsaturated fatty acids) as well as vitamin E and methionine supplementation altered blood cholesterol lipoprotein profiles; 2) in vitro oxidation parameters including LDL (lag time and diene production) and plasma hydroperoxide formations were affected by vitamin E and methionine supplementation; and 3) plasma homocysteine concentrations were influenced by supplemental methionine and the inclusion of dietary saturated fat.     

Antioxidant and hypolipidaemic activity of a herbal formulation--liposem

The efficacy of Liposem, a polyherbal formulation, as an antioxidant and hypolipidaemic drug was evaluated in diet induced hyperlipidaemia in rats. The methanolic extract of Liposem was found to scavenge hydroxyl and superoxide free radicals, the IC50 required being 70.5 and 45.0 microg respectively. The lipid peroxidation in rat liver homogenate induced by Fe2+ ascorbate system was also found inhibited (50%) by 273.5 microg of the extract. The hypolipidaemic effect was assessed by serum lipid profile in dietary hyperlipidaemic rats and found to have decreased dose dependently in all the four different concentrations of administration (100, 200, 300 and 400 mg/kg body wt). Liposem significantly raised high-density lipoprotein (HDL) cholesterol and the HDL/low density lipoprotein + very low-density lipoprotein (VLDL+LDL) ratio. The atherogenic index and the reduction in body weight were significant, indicating the effectiveness against hyperlipidaemia and obesity. These results reveal the therapeutic potential of Liposem against the vascular intimal damage and diet induced hyperlipidaemia leading to the various types of cardio vascular diseases.     

Regulation of hepatic secretion of very low density lipoprotein by dietary cholesterol.

Male rats were fed a cholesterol-free diet or the same diet supplemented with either 0.05, 0.1, 0.25, 0.5, 1, or 2% C for 21 days to investigate the effects of cholesterol on secretion of very low density lipoprotein (VLDL). Cholesterol feeding increased plasma and hepatic concentrations of triglyceride (TG) and cholesteryl esters (CE) in a dose-dependent manner. Plasma VLDL and low density lipoprotein (LDL) lipids were elevated by cholesterol feeding, while the high density lipoprotein (HDL) lipids were reduced. The secretion of the VLDL by perfused livers from these cholesterol-fed rats was examined to establish the relationship between the accumulation of lipids in the liver and the concurrent hyperlipemia. Liver perfusions were carried out for 4 h with a medium containing bovine serum albumin (3% w/v), glucose (0.1% w/v), bovine erythrocytes (30% v/v), and a 10-mCi 3H2O initial pulse. Oleic acid was infused to maintain a concentration of 0.6 mM. Hepatic secretion of VLDL-TG, PL (phospholipid), free cholesterol (FC), and CE increased in proportion to dietary cholesterol and was maximal at 0.5% cholesterol in these experiments in which TG synthesis was stimulated by oleic acid. Secretion of VLDL protein and apoB by the perfused liver was also increased. The molar ratios of surface (sum of PL and cholesterol) to core (sum of TG and CE) lipid components of the secreted VLDL, regardless of cholesterol feeding, were the same, as were the mean diameters of the secreted particles. The molar ratios of surface to core lipid of VLDL isolated from the plasma also were not affected by cholesterol feeding. During perfusion with oleic acid of livers from the rats fed the higher levels of cholesterol, the hepatic concentration of CE decreased, while the level of TG was not changed. We conclude that the hypercholesterolemia and hypertriglyceridemia that occur in vivo from cholesterol feeding, concurrent with accumulation of CE and TG in the liver, must result, in part, from increased hepatic secretion of all VLDL lipids and apoB. The VLDL particles produced by the liver of the cholesterol-fed rat are assembled without modification of the surface lipid ratios (PL/FC), but contain a greater proportion of cholesteryl esters compared to triglyceride in the core, because of the stimulated transport of CE from the expanded pool in the liver.(ABSTRACT TRUNCATED AT 400 WORDS)     

Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and in the liver

Scavenger receptor class B, type I (SRBI) is a key regulator of high density lipoprotein (HDL) metabolism. It facilitates the efflux of cholesterol from cells in peripheral tissues to HDL and mediates the selective uptake of cholesteryl esters from HDL in the liver. We investigated the effects of SRBI deficiency in the arterial wall and in the liver using SRBI-deficient mice and wild-type littermates fed a Western-type diet. The SRBI-deficient mice showed massive accumulation of cholesterol-rich HDL in the circulation, reflecting impaired delivery to the liver. Strikingly, SRBI deficiency did not alter hepatic cholesterol (ester) content nor did it affect the expression of key regulators of hepatic cholesterol homeostasis, including HMG-CoA reductase, the low density lipoprotein receptor, and cholesterol 7alpha-hydroxylase. However, a approximately 40% reduction in biliary cholesterol content was observed, and the expression of ABCG8 and ABCG5, ATP half-transporters implicated in the transport of sterols from the liver to the bile, was attenuated by 70 and 35%, respectively. In contrast to the situation in the liver, SRBI deficiency did result in lipid deposition in the aorta and atherosclerosis. Vascular mRNA analysis showed increased expression of inflammatory markers as well as of genes involved in cellular cholesterol homeostasis. Our data show that, although hepatic cholesterol homeostasis is maintained upon feeding a Western-type diet, SRBI deficiency is associated with de-regulation of cholesterol homeostasis in the arterial wall that results in an increased susceptibility to atherosclerosis.     

Activation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase during high fat diet feeding

The liver plays a central role in regulating cholesterol homeostasis. High fat diets have been shown to induce obesity and hyperlipidemia. Despite considerable advances in our understanding of cholesterol metabolism, the regulation of liver cholesterol biosynthesis in response to high fat diet feeding has not been fully addressed. The aim of the present study was to investigate mechanisms by which a high fat diet caused activation of liver 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) leading to increased cholesterol biosynthesis. Mice were fed a high fat diet (60% kcal fat) for 5 weeks. High fat diet feeding induced weight gain and elevated lipid levels (total cholesterol and triglyceride) in both the liver and serum. Despite cholesterol accumulation in the liver, there was a significant increase in hepatic HMG-CoA reductase mRNA and protein expression as well as enzyme activity. The DNA binding activity of sterol regulatory element binding protein (SREBP)-2 and specific protein 1 (Sp1) were also increased in the liver of mice fed a high fat diet. To validate the in vivo findings, HepG2 cells were treated with palmitic acid. Such a treatment activated SREBP-2 as well as increased the mRNA and enzyme activity of HMG-CoA reductase leading to intracellular cholesterol accumulation. Inhibition of Sp1 by siRNA transfection abolished palmitic acid-induced SREBP-2 and HMG-CoA reductase mRNA expression. These results suggest that Sp1-mediated SREBP-2 activation contributes to high fat diet induced HMG-CoA reductase activation and increased cholesterol biosynthesis. This may play a role in liver cholesterol accumulation and hypercholesterolemia.     

银灵通胶囊调节实验性高脂饮食大鼠血脂的研究

目的:探究银灵通胶囊对脂质代谢的影响及其机制。方法:建立大鼠高脂模型,用药后检测其血脂、丙二醛(MDA)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)的活性,检测肝脏组织的高密度脂蛋白受体SR-BI、低密度脂蛋白受体(LDLR)、氧化低密度脂蛋白(ox-LDH)受体CD36蛋白表达的mRNA表达水平,检测血管组织学变化。结果:高脂饮食明显升高大鼠血清中总胆固醇(CH)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和动脉硬化指数(AI值),银灵通胶囊组可降低上述指标,且呈一定的浓度依赖;高脂饮食可增加肝脏中SR-BI及CD36表达,降低LDLR表达,银灵通胶囊引起SR-BI的过度表达,使LDLR表达增加,CD36表达下降。高脂饮食使血清中MDA的含量增加,给予银灵通胶囊后,明显降低血清MDA的含量。结论:银灵通胶囊具有调节脂质代谢,抗动脉粥样硬化(AS)及抗脂质过氧化作用。其机制与银灵通胶囊能引起肝脏中SR-BI的过度表达及LDLR表达增加,降低肝脏中CD36表达和血清MDA含量有关。     

Lipoprotein, apolipoprotein, and lipolytic enzyme changes following estrogen administration in postmenopausal women

To test whether estrogen can modulate the cholesterolemic response to an Occidental diet, six healthy postmenopausal women were studied for 84 days while ingesting a solid food diet of constant composition high in cholesterol content (995 mg/d). In the middle of the study, estrogen (17 alpha-ethinyl estradiol, 1 microgram/kg per day) was administered orally. Ingestion of the diet for the initial 28 days did not alter lipoprotein lipid or apolipoprotein (apo) levels. However, with just 4 days of estrogen use there were significant decreases in apoE (-36%), low density lipoprotein cholesterol (-26%), and postheparin plasma hepatic triglyceride lipase activity (HTGL) (-61%), and an increase in high density lipoprotein (HDL) triglyceride (72%). These changes persisted throughout the estrogen use. The percent change in HTGL with 4 days of estrogen correlated inversely with the percent change in HDL triglyceride (rs = -0.94). After 28 days of estrogen there were also significant increases in HDL cholesterol (21%), HDL2 cholesterol (42%), apoA-I (37%), and apoA-II (9%), and a decrease in apoB (-11%). The level of apoE at this juncture correlated inversely with the level of HDL cholesterol (rs = -0.90), and the levels of HTGL and apoA-I correlated with HDL2 cholesterol (rs = -0.89 and rs = 0.89, respectively). Thus, HTGL may play a role in both the early estrogen-related changes in HDL triglyceride and apoE and the late estrogen-related changes in HDL cholesterol, apoA-I, and apoA-II.     

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.     

Reduction in VLDL, but not HDL, in plasma of rats deficient in choline

We have analyzed plasma lipoprotein levels in young male rats fed a choline-deficient diet for 3 days. We confirmed previous studies that choline deficiency promotes 6.5-fold accumulation of triacyglycerol in the liver (23.9 +/- 6.0 versus 3.69 +/- 0.92 mumol/g liver) and reduction of triacylglycerol concentration in plasma by 60% (0.17 +/- 0.04 versus 0.46 +/- 0.10 mumol/mL plasma). Agarose gel electrophoresis showed that the plasma very low density lipoprotein (VLDL) levels were reduced in choline-deficient rats, but the concentration of plasma high density lipoproteins (HDL) was not affected. Sodium dodecyl sulfate - polyacrylamide gel electrophoresis of fractionated plasma lipoproteins revealed that the concentrations of apolipoproteins (apo) BH, BL, and E in VLDL from choline-deficient rats were 37.1, 11.0, and 37.2% of normal levels, respectively. In contrast, the amount of apo A-I, the major one in HDL, was almost unchanged. Correspondingly, there were decreased lipid (mainly phosphatidylcholine and triacylglycerol) levels in VLDL from choline-deficient rats, but no change in the levels of phosphatidylcholine, cholesterol, and cholesterol ester in HDL. There were similar levels of apo B and E (components of VLDL) in homogenates of livers from normal and choline-deficient rats, as determined by immunoblotting. These results support the hypothesis that choline deficiency causes reduction of VLDL, but not HDL, levels in plasma as a consequence of impaired hepatic VLDL secretion.     

Hypocholesterolemic effects of phenolic-rich extracts of Chemlali olive cultivar in rats fed a cholesterol-rich diet

This study was designed to test the lipid-lowering and the antioxidative activities of green and black olive phenolic extracts. Wistar rats fed a standard laboratory diet or a cholesterol-rich diet for 16 weeks were used. The serum lipid levels, the malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) as well as that of catalase (CAT) were examined. The cholesterol-rich diet induced hypercholesterolemia that was manifested in the elevation of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C). Administration of aqueous methanol and ethyl acetate extracts of green olives and ethyl acetate extract of black olives significantly lowered the serum levels of TC and LDL-C, while increasing the serum level of high density lipoprotein cholesterol (HDL-C). Furthermore, the content of MDA in liver, heart and kidney decreased significantly after oral administration of green and black olive extracts compared with those of rats fed a cholesterol-rich diet. In addition, olive extracts increased CAT and SOD activities in liver. These results suggested that the hypocholesterolemic effect of green and black olive extracts might be due to their abilities to lower serum cholesterol level as well as to slow down the lipid peroxidation process and to enhance the antioxidant enzyme activity.