Effects of dietary soybean lecithin on plasma lipid transport and hepatic cholesterol metabolism in rats

Dietary lecithin can stimulate bile formation and biliary lipid secretion, particularly cholesterol output in bile. Studies also suggested that the lecithin-rich diet might modify hepatic cholesterol homeostasis and lipoprotein metabolism. Therefore, we examined hepatic activities of 3-hydroxy-3 methylglutaryl coenzyme A reductase "HMG -CoA reductase", cholesterol 7 alpha-hydroxylase and acyl-CoA: cholesterol acyltransferase "ACAT" as well as plasma lipids and lipoprotein composition in rats fed diets enriched with 20% of soybean lecithin during 14 days. We also evaluated the content of hepatic canalicular membrane proteins involved in lipid transport to the bile (all P-glycoproteins as detected by the C 219 antibody and the sister of P-glycoprotein "spgp" or bile acid export pump) by Western blotting. As predicted, lecithin diet modified hepatic cholesterol homeostasis. The activity of hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase was enhanced by 30 and 12% respectively, while microsomal ACAT activity showed a dramatic decrease of 75%. As previously reported from ACAT inhibition, the plasma level and size of very low-density lipoprotein (VLDL) were significantly decreased and bile acid pool size and biliary lipid output were significantly increased. The canalicular membrane content of lipid transporters was not significantly affected by dietary lecithin. The current data on inhibition of ACAT activity and related metabolic effects by lecithin mimic the previously reported effects following drug-induced inhibition of ACAT activity, suggesting potential beneficial effects of dietary lecithin supplementation in vascular disease.     

Hypolipidemic action of taurine in rats.

The effect of taurine on the serum and liver cholesterol and triglyceride levels was studied in rats fed cholesterol plus cholic acid. Four groups of 4 weeks old rats were fed control diet, hypercholesterolemic diet (HCD), HCD + 1% taurine or HCD + 2% taurine for 8 weeks. Addition of taurine in HCD diet showed a significant reduction not only in serum total cholesterol and triglyceride levels but also in liver total cholesterol, lipid and triglyceride contents compared to the animals fed HCD alone. Histological examination of organs of these animals showed severe fatty vacuolation in livers and signet ring type vacuolation in kidneys of rats fed HCD. Taurine showed ameliorating effect on these abnormalities. The animals fed taurine in HCD also showed increased bile and sterol excretion in faeces compared to rats fed HCD alone. Taurine showed significant hypocholesterolemia in rats probably by enhancing the catabolism of cholesterol and reducing the absorption of dietary cholesterol.     

Black and green tea improves lipid profile and lipid peroxidation parameters in Wistar rats fed a high-cholesterol diet

In the present study, the efficacy of black tea (BT) and green tea (GT) was studied in relation to serum and hepatic oxidative abnormalities in hypercholesterolemic rats. Hypercholesterolemia was induced in male Wistar rats (8 week old) by feeding them with a high-cholesterol diet (HCD) for 35 days. The experimental rats were given BT and GT as a supplement (7 g/L) via drinking water. Increased hepatic and serum lipid profile along with abnormalities in oxidative marker, with a concomitant increase in the body weight, food intake, and food efficiency, were seen in hypercholesterolemic rats. Following the supplementation of BT and GT to rats fed with HCD, significantly lower levels of serum and hepatic cholesterol, triglycerides, serum low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol levels were observed, when compared with hypercholesterolemic group. Further, significantly lower levels in the serum and hepatic lipid peroxidation, body weight gain, and food efficiency were observed in BT and GT group when compared with control and HCD fed group. However, no such significant changes were observed in the food intake upon supplementation with BT and GT. These results suggest that supplementation of BT and GT may protect against the serum and hepatic abnormalities in hypercholesterolemic rats.     

Role of lupeol and lupeol linoleate on lipemic-oxidative stress in experimental hypercholesterolemia

Epidemiological studies have shown that there is a positive correlation between the incidence of coronary heart disease (CHD) and the blood cholesterol level. To study the effect of plant derived triterpene, lupeol and its ester lupeol linoleate, on blood lipid status and oxidant stress in heart and hemolysate, male albino Wistar rats were fed high cholesterol diet (normal rat chow supplemented with 4% cholesterol and 1% cholic acid; HCD) for 30 days. A significant increase (p<0.05) in plasma total cholesterol (4.22 fold) and triglycerides (1.7 fold) was observed in HCD fed rats, along with elevated LDL (3.56 fold) and VLDL (1.99 fold) cholesterol and decreased HDL cholesterol (34.14%). Treatment with lupeol and its derivative normalized the lipid profile. The significant increase (p<0.05) in lipid peroxidation (LPO) was paralleled by significantly diminished (p<0.05) activities of antioxidant enzymes (SOD, CAT and GPx) and decreased (p<0.05) concentration of antioxidant molecules (GSH, Vit C and Vit E) in cardiac tissue and hemolysate of HCD fed rats. The oxidative tissue injury in hypercholesterolemic rats was substantiated by the increase in cardiac marker, serum CPK and the drop in its activity in the heart tissue. Lupeol and lupeol linoleate treatment decreased the LPO levels and increased enzymatic and nonenzymatic antioxidants. CPK activity in the treated group was comparable with that of the control. These observations highlight the beneficial effects of the triterpene, lupeol and its linoleate ester derivative, in ameliorating the lipidemic-oxidative abnormalities in the early stage of hypercholesterolemic atherosclerosis.     

Mitigating role of lupeol and lupeol linoleate on hepatic lipemic-oxidative injury and lipoprotein peroxidation in experimental hypercholesterolemia

In the present study, the role of pentacyclic triterpenes, lupeol and its ester lupeol linoleate, was studied in relation to hepatic oxidative abnormalities and lipoprotein peroxidation in hypercholesterolemic rats. Hypercholesterolemia was induced in male Wistar rats by feeding them with high cholesterol diet (4% cholesterol + 1% cholic acid; HCD) for 30 days. Pentacyclic triterpenes, lupeol and lupeol linoleate were supplemented (50 mg/kg body wt/day) during the last 15 days. After the experimental period, there was a significant depression in hepatic activities of antioxidant enzymes, SOD (38.39%), CAT (25.03%) and GPx (30.26%) along with a marked fall in the levels of non-enzymic antioxidant molecules GSH (31.39%), vitamin C (46.07%) and vitamin E (42.28%), with a concomitant increase (p<0.001) in lipid peroxidation and in the activities of serum alkaline phosphatase, lactate dehydrogenase and aminotransferases when compared to controls. Treatment with triterpenes decreased lipid peroxidation and reverted the activities of antioxidants (p<0.001 and p<0.01) and marker enzymes to near control. Histopathological findings further confirmed the hepatoprotective nature of triterpenes by showing the normal architecture in treated rats, as against the fatty cellular changes in HCD fed rats. Further, the susceptibility of apo-B containing lipoprotein to oxidation by copper and Fenton’s reagent was increased in in vitro condition in HCD fed rats, whereas the lipoproteins were less susceptible to oxidation in triterpenes treated animals. Therefore, it may be concluded that lupeol and its ester afford protection against the hepatic abnormalities and lipoprotein peroxidation in hypercholesterolemic rats.     

Effects of increased dietary cholesterol with carbohydrate restriction on hepatic lipid metabolism in Guinea pigs

Excessive lipid accumulation within hepatocytes, or hepatic steatosis, is the pathognominic feature of nonalcoholic fatty liver disease (NAFLD), a disease associated with insulin resistance and obesity. Low-carbohydrate diets (LCD) improve these conditions and were implemented in this study to potentially attenuate hepatic steatosis in hypercholesterolemic guinea pigs. Male guinea pigs (n = 10 per group) were randomly assigned to consume high cholesterol (0.25 g/100 g) in either a LCD or a high-carbohydrate diet (HCD) for 12 wk. As compared with HCD, plasma LDL cholesterol was lower and plasma triglycerides were higher in animals fed the LCD diet, with no differences in plasma free fatty acids or glucose. The most prominent finding was a 40% increase in liver weight in guinea pigs fed the LCD diet despite no differences in hepatic cholesterol or triglycerides between the LCD and the HCD groups. Regardless of diet, all livers had severe hepatic steatosis on histologic examination. Regression analysis suggested that liver weight was independent of body weight and liver mass was independent of hepatic lipid content. LCD livers had more proliferating hepatocytes than did HCD livers, suggesting that in the context of cholesterol-induced hepatic steatosis, dietary carbohydrate restriction enhances liver cell proliferation.     

Protective effect of lupeol and lupeol linoleate in hypercholesterolemia associated renal damage

The association between hypercholesterolemia and kidney damage has been well known for last few decades. The oxidative stress and inflammatory responses are involved in renal injury, which is upregulated in hypercholesterolemic condition. The present study is aimed to evaluate the possible effect of lupeol and its ester derivative, lupeol linoleate in renal damage associated with hypercholesterolemic rats. Hypercholesterolemia was induced in male Wistar rats by feeding them with a high cholesterol diet (HCD) comprising normal rat chow supplemented with 4% cholesterol and 1% cholic acid for 30 days. Lupeol and lupeol linoleate were supplemented (50 mg/kg body wt/day) to HCD fed rats during the last 15 days. Increased levels of renal total cholesterol, triglycerides and phospholipids, along with altered serum biochemical parameters of tissue injury indices and elevated activities of renal marker enzymes (lactate dehydrogenase and alkaline phosphatase) were noted in HCD fed rats. Elevated lipid peroxidation levels coupled with decreased antioxidant status (enzymatic and non enzymatic antioxidants) were observed in hypercholesterolemic rats, which indicate the onset of oxidative changes in the renal tissue. Renal lysosomal acid hydrolase activities (ACP, beta-Glu, beta-Gal, NAG and Cat-D) and acute phase proteins like C-Reactive protein and fibrinogen were significantly increased in HCD fed rats, which further indicates the heightening of inflammation. In addition, histopathological findings also confirmed the renal damage in hypercholesterolemic condition. Lupeol and lupeol linoleate effectively reverted the above abnormalities and was comparable with that of the control. These observations highlight the protective effect of lupeol and its ester derivative in ameliorating the renal injury associated with hypercholesterolemia.     

Regulation of hepatic cholesterol ester hydrolase and acyl-coenzyme A:cholesterol acyltransferase in the rat

Cholesterol exists within the hepatocyte as free cholesterol and cholesteryl ester. The proportion of intrahepatic cholesterol in the free or ester forms is governed in part by the rate of cholesteryl ester formation by acyl-coenzyme A:cholesterol acyltransferase (ACAT) and cholesteryl ester hydrolysis by neutral cholesterol ester (CE) hydrolase. In other cell types both ACAT and CE hydrolase activities are regulated in response to changes in the need for cellular free cholesterol. In rats, we performed a variety of experimental manipulations in order to vary the need for hepatic free cholesterol and to examine what effect, if any, this had on the enzymes that govern cholesteryl ester metabolism. Administration of a 20-mg bolus of lipoprotein cholesterol or a diet supplemented with 2% cholesterol resulted in an increase in microsomal cholesteryl ester content with little change in microsomal free cholesterol. This was accomplished by an increase in cholesteryl esterification as measured by ACAT but no change in CE hydrolase activity. An increased need for hepatic free cholesterol was experimentally induced by intravenous bile salt infusion or cholestyramine (3%) added to the diet. ACAT activity was decreased with both experimental manipulations compared to controls, while CE hydrolase activity did not change. Microsomal cholesteryl ester content decreased significantly with little change in microsomal free cholesterol content. Addition of exogenous liposomal cholesterol to liver microsomes from cholestyramine-fed and control rats resulted in a 784 +/- 38% increase in ACAT activity. Nevertheless, the decrease in ACAT activity with cholestyramine feeding was maintained. These studies allowed us to conclude that changes in hepatic free cholesterol needs are met in part by regulation of the rate of cholesterol esterification by ACAT without a change in the rate of cholesteryl ester hydrolysis by CE hydrolase.     

Dietary effect of Pleurotus eryngii on biochemical function and histology in hypercholesterolemic rats

This work was conducted to investigate diet supplement of king oyster mushroom fruiting bodies on biochemical and histological changes in hypercholesterolemic rats. Six-week old female Sprague–Dawley albino rats were divided into three groups of 10 rats each. The feeding of 5% powder of the fruiting bodies of Pleurotus eryngii to hypercholesterolemic rats reduced their plasma total cholesterol, triglyceride, low-density lipoprotein, total lipid, phospholipids, and LDL/HDL ratio by 24.05%, 46.33%, 62.50%, 24.63%, 19.22%, and 57.14%, respectively. Mushroom also significantly reduced body weight in hypercholesterolemic rats. However, it had no adverse effects on plasma albumin, total bilirubin, direct bilirubin, creatinine, blood urea nitrogen, uric acid, glucose, total protein, calcium, sodium, potassium, chloride, inorganic phosphate, magnesium, and enzyme profiles. Feeding mushroom increased total lipid and cholesterol excretion in feces. The plasma lipoprotein fraction, separated by agarose gel electrophoresis, indicated that P. eryngii significantly reduced plasma β and pre-β-lipoprotein, while increased α-lipoprotein. A histological study of hepatic cells by conventional hematoxylin–eosin and oil red O staining showed normal findings for mushroom-fed hypercholesterolemic rat. The present study suggests that 5% P. eryngii diet supplement provided health benefits by acting on the atherogenic lipid profile in hypercholesterolaemic rats. Therefore, king oyster mushroom could be recommended as a natural cholesterol lowering substance within the human diet.     

Structured triglycerides containing caprylic (8:0) and oleic (18:1) fatty acids reduce blood cholesterol concentrations and aortic cholesterol accumulation in hamsters

The effects of structured triglycerides containing one long chain fatty acid (oleic acid, C18:1) and one short chain saturated fatty acid (caprylic acid, 8:0) on lipidemia, liver and aortic cholesterol, and fecal neutral sterol excretion were investigated in male Golden Syrian hamsters fed a hypercholesterolemic regimen consisting of 89.9% commercial ration to which was added 10% coconut oil and 0.1% cholesterol (w/w). After 2 weeks on the HCD diet, the hamsters were bled, following an overnight fast (16 h) and placed into one of three dietary treatments of eight animals each based on similar plasma cholesterol levels. The hamsters either continued on the HCD diet or were placed on diets in which the coconut oil was replaced by one of two structured triglycerides, namely, 1(3),2-dicaproyl-3(1)-oleoylglycerol (OCC) or 1,3-dicaproyl-2-oleoylglycerol (COC) at 10% by weight. Plasma total cholesterol (TC) in hamsters fed the OCC and COC compared to the HCD were reduced 40% and 49%, respectively (P<0.05). Similarly, hamsters fed the OCC and COC diets reduced their plasma nonHDL cholesterol levels by 47% and 57%, respectively (P<0.05), compared to hamsters fed the HCD after 2 weeks of dietary treatment. Although hamsters fed the OCC (-26%) and COC (-32%) had significantly lower plasma HDL levels compared to HCD, (P<0.05), the plasma nonHDL/HDL cholesterol ratio was significantly lower (P<0.05) compared to the HCD for the OCC-fed (-27%) and the COC-fed (-38%) hamsters, respectively. Compared to the HCD group, aortic esterified cholesterol was 20% and 53% lower for the OCC and COC groups, respectively, with the latter reaching statistical significance, P<0.05. In conclusion, the hamsters fed the structured triglyceride oils had lower blood cholesterol levels and lower aortic accumulation of cholesterol compared to the control fed hamsters.     

The possible alleviating effect of garlic supplement on the neural retina in a rat model of hypercholesterolemia: A histological and immunohistochemical study

The purpose of this work was to prove that oxidative stress is the main mechanism responsible for retinal neurodegenerative changes, subsequent apoptosis, and inflammatory cytokine release in rats fed with a high cholesterol diet (HCD) and determine the role of garlic in alleviating these changes. Forty rats were equally divided into four groups: control, garlic-treated (positive control), HCD, and HCD + garlic-treated (HCD + G). By the end of the experiment (24 weeks) blood samples were collected for assessment of serum lipid profile, oxidative stress parameters, and plasma levels of IL-6 and TNF-α. Both eyes of the rats were enucleated; one was used for light microscopic examination and the other for electron microscopic examination. There was a significant increase in the levels of serum lipids, oxidative stress parameters, IL-6 and TNF-α, and area of expression of caspase-3 in the HCD group compared to both the control and HCD + G groups. Histological examination revealed degenerative changes in all layers of the neural retina in the HCD group. Garlic administration resulted in a significant improvement in the biochemical, immunohistochemical, and histological characteristics of hypercholesterolemic rats. These findings support the hypotheses that garlic has strong antioxidant, anti-apoptotic, and anti-inflammatory properties. Garlic ameliorates the neurodegenerative changes in the neural retina of hypercholesteremic rats.Key words: Hypercholesterolemia, garlic, neural retina     

Naringenin 7-O-cetyl ether as inhibitor of HMG-CoA reductase and modulator of plasma and hepatic lipids in high cholesterol-fed rats

Numerous studies in vitro have shown a close relationship between the chemical structure and biologic activity of flavonoids, whereby their basic structure is modified to increase or decrease their biologic activity. The effects of naringenin (1) and its synthetic derivative, naringenin 7-O-cetyl ether (2), on the lipid profile, the cholesterol-regulating enzyme activity and the excretion of sterol were compared in rats fed a high-cholesterol (1% wt/wt) diet. Either 1 or 2 was supplemented with a high-cholesterol diet for 6 weeks at a dose of 0.073 mmol/100g diet. The supplementation of 1 or 2 significantly lowered the levels (mean+/-SE) of the plasma total cholesterol (4.93+/-0.19 and 4.75+/-0.16 mmol/L vs 5.87+/-0.36 mmol/L, p<0.05) and hepatic triglyceride (0.12+/-0.01 and 0.11+/-0.01 mmol/g vs 0.18+/-0.01 mmol/g, p<0.05) and cholesterol (0.23+/-0.01 and 0.21+/-0.01 mmol/g vs 0.31+/-0.01 mmol/g, p<0.05) compared to those of the control. The compound 1 or 2 supplementation appeared to decrease the excretion of neutral sterols. The plasma HDL-cholesterol concentration and ratio of HDL to total cholesterol were significantly higher in 1 and 2 groups than in control group. Although the biological effect of 2 on inhibiting hepatic HMG-CoA reductase and ACAT activities was only significant compared to the control group, both compounds exhibited a significant hypocholesterolemic effect in rats fed a high-cholesterol diet. The results suggest that cholesterol biosynthesis and esterification were concomitantly reduced by 2, as indicated by the decreased HMG-CoA reductase and ACAT activities.     

Effect of high levels of selected dietary essential amino acids on hypercholesterolemia and down-regulation of hepatic LDL receptors in rabbits.

Earlier studies showed that the elevation of serum total and low density lipoprotein (LDL) cholesterol levels produced in rabbits by feeding high levels of a casein amino acid mixture in a cholesterol-free, semipurified diet was due primarily to the essential amino acids (EAA) in the mixture. Replacing all of the non-essential amino acids in the mixture by glutamic acid (45% EAA+Glu) had little effect on the hypercholesterolemia produced by the EAA. Experiments designed to identify the hypercholesterolemic EAA showed that (i) feeding high levels of ketogenic EAA only (45% EketoAA) gave a substantial but variable elevation of serum total and LDL cholesterol and (ii) feeding high levels of all EAA except arginine (45% EAA-Arg) gave a particularly strong hypercholesterolemic response. In rabbits fed the 45% EAA-Arg diet and to a lesser extent, in those fed the 45% EAA+Glu diet, EDTA-sensitive binding of 125I-LDL to hepatic membranes in vitro was reduced compared to a control, low-cholesterolemic group fed all essential and non-essential amino acids at a level corresponding to 14.7% casein, indicating that the hypercholesterolemia was associated with down-regulation of hepatic LDL receptors.     

Hypocholesterolemic effect of protein prepared from Phaseolus aconitifolius (Jacq.)

Hypocholesterolemic effect of protein concentrate (PC) prepared from moth bean (Phaseolus aconitifolius Jacq.) seeds relative to that of pigeon pea PC and casein were investigated in rats fed on hypercholesterolemic diet containing two per cent cholesterol. The test diets containing casein and legume PCs at 10% protein level were fed to albino rats (Wistar strain) for 45 days. Compared to casein, the two legume PCs produced significantly lower levels of liver total lipid and cholesterol levels except that pigeon pea PC produced only non-significant decrease of total cholesterols in the heart. In addition, the legume PCs produced significantly lower levels of serum triglycerides and total lipids as well as lower levels of total and low-density lipoprotein cholesterol. Moreover, only moth bean PC produced a significantly higher level of serum high-density lipoprotein cholesterol. Generally, PC of moth bean seemed to be more potent at lowering the elevated hepatic and serum lipids and cholesterol levels, which were attributed to the amino acid profile of this lesser-known legume as these indices well correlated with serum cholesterol levels.     

Solid monounsaturated diet lowers LDL unsaturation trait and oxidisability in hypercholesterolemic (type IIb) patients

Lowering high cholesterol concentration decreases the probability of atherosclerotic-related pathology onset. MUFA and PUFA decrease total plasma and LDL cholesterol but PUFA may increase the susceptibility of LDL to undergo oxidative modifications thus becoming more atherogenetic. Olive oil, the predominant fat source in Mediterranean diet, may combine the advantages of both lowering cholesterol level and decreasing LDL susceptibility to oxidation. We studied the effects of feeding MUFA vs PUFA enriched diet on LDL composition and feature in hypercholesterolemic (IIb) patients. Antioxidant values remained constant during the study while LDL fatty acids composition reflected the dietary intake: MUFA concentration increased 11% whereas PUFA decreased 10% after olive oil diet (p < 0.05). PUFA/MUFA ratio and the unsaturation index were lower at the end of MUFA-enriched diet. The challenge, in vitro, of oleate-enriched LDL with Cu2- yielded to lower lag-phase (p < 0.05) in diene conjugated production; the same LDL gave lower lipid hydroperoxide contents after exposition to AAPH. We conclude that oleate-enriched LDL and with lower PUFA content were more resistant to oxidative modifications, as measured by different peroxidation indexes. This feature acquired with the diet may be an useful tool for lowering LDL oxidation and indirectly their atherogenicity.     

Lecithin:cholesterol acyltransferase deficiency protects against cholesterol-induced hepatic endoplasmic reticulum stress in mice

We recently reported that lecithin:cholesterol acyltransferase (LCAT) knock-out mice, particularly in the LDL receptor knock-out background, are hypersensitive to insulin and resistant to high fat diet-induced insulin resistance (IR) and obesity. We demonstrated that chow-fed Ldlr-/-xLcat+/+ mice have elevated hepatic endoplasmic reticulum (ER) stress, which promotes IR, compared with wild-type controls, and this effect is normalized in Ldlr-/-xLcat-/- mice. In the present study, we tested the hypothesis that hepatic ER cholesterol metabolism differentially regulates ER stress using these models. We observed that the Ldlr-/-xLcat+/+ mice accumulate excess hepatic total and ER cholesterol primarily attributed to increased reuptake of biliary cholesterol as we observed reduced biliary cholesterol in conjunction with decreased hepatic Abcg5/g8 mRNA, increased Npc1l1 mRNA, and decreased Hmgr mRNA and nuclear SREBP2 protein. Intestinal NPC1L1 protein was induced. Expression of these genes was reversed in the Ldlr-/-xLcat-/- mice, accounting for the normalization of total and ER cholesterol and ER stress. Upon feeding a 2% high cholesterol diet (HCD), Ldlr-/-xLcat-/- mice accumulated a similar amount of total hepatic cholesterol compared with the Ldlr-/-xLcat+/+ mice, but the hepatic ER cholesterol levels remained low in conjunction with being protected from HCD-induced ER stress and IR. Hepatic ER stress correlates strongly with hepatic ER free cholesterol but poorly with hepatic tissue free cholesterol. The unexpectedly low ER cholesterol seen in HCD-fed Ldlr-/-xLcat-/- mice was attributable to a coordinated marked up-regulation of ACAT2 and suppressed SREBP2 processing. Thus, factors influencing the accumulation of ER cholesterol may be important for the development of hepatic insulin resistance.     

Alpha-asarone inhibits HMG-CoA reductase, lowers serum LDL-cholesterol levels and reduces biliary CSI in hypercholesterolemic rats.

Our results showed that alpha-asarone was an inhibitor of hepatic HMG-CoA reductase and that the administration of alpha-asarone at 80 mg/kg body wt. for 8 days decreased serum cholesterol by 38% (p < 0.001) in hypercholesterolemic rats. This alpha-asarone treatment affected mainly the serum LDL-cholesterol levels, leaving serum HDL-cholesterol lipoproteins unaffected, with a consequent decrease of 74% in the LDL/HDL ratio. In addition, alpha-asarone especially stimulated bile flow in hypercholesterolemic rats (60%), increasing the secretion of bile salts, phospholipids and bile cholesterol. The drug also reduced the cholesterol levels of gallbladder bile, whereas the concentration of phospholipids and bile salts increased only slightly, leading to a decrease in the cholesterol saturation index (CSI) of bile in the hypercholesterolemic rats. This CSI decrease and the increase in bile flow induced by alpha-asarone may account for the cholelitholytic effect of alpha-asarone. It seems that alpha-asarone induced clearance of cholesterol from the bloodstream and that the excess of hepatic cholesterol provided by LDL-cholesterol is diverted to bile sterol secretion via a bile choleresis process. The inhibition of HMG-CoA reductase and the increase in bile flow induced by alpha-asarone, as well as the decrease in the CSI, could then explain the hypocholesterolemic and cholelitholytic effects of alpha-asarone.     

Changes in both acyl-CoA:cholesterol acyltransferase activity and microsomal lipid composition in rat liver induced by distal-small-bowel resection.

The acyl-CoA:cholesterol acyltransferase (ACAT) activity and lipid composition of hepatic microsomal membrane were investigated 6 weeks after both 50 and 75% distal-small-bowel resection (SBR). A significant decrease in hepatic cholesteryl ester levels was observed after SBR, with a significant increase in the cholesteryl ester content of the livers of 75% SBR compared with the 50% SBR. Hepatic total acylglycerols, free cholesterol and phospholipid levels were not modified after the surgical operation. Microsomal free cholesterol was increased after both 50 and 75% SBR. However, a decrease in both microsomal ACAT activity and cholesteryl ester levels were found in microsomes (microsomal fractions) of resected rats, both changes being higher after 75 than after 50% resection. The total phospholipid content of the microsomes did not change after the surgical operation. The microsomal phospholipid fatty acid composition indicated higher changes after 75 than after 50% SBR. These results demonstrated that, in resected animals: (1) the activity of the enzyme responsible for catalysing cholesterol esterification (ACAT) is decreased, and (2) hepatic microsomal free cholesterol does not appear to influence the activity of ACAT.     

Chronic intermittent hypoxia induces atherosclerosis by NF-κB-dependent mechanisms

Chronic intermittent hypoxia (CIH) causes atherosclerosis in mice fed a high cholesterol diet (HCD). The mechanisms by which CIH promotes atherosclerosis are incompletely understood. This study defined the mechanistic role of NF-κB pathway in CIH+HCD induced atherosclerosis. Wild type (WT) and mice deficient in the p50 subunit of NF-κB (p50-KO) were fed normal chow diet (ND) or HCD, and exposed to sham or CIH. Atherosclerotic lesions on the en face aortic preparation and cross-sections of aortic root were examined. In WT mice, neither CIH nor HCD exposure alone caused, but CIH+HCD caused evident atherosclerotic lesions on both preparations after 20weeks of exposure. WT mice on ND and exposed to CIH for 35.6weeks did not develop atherosclerotic lesions. P50 gene deletion diminished CIH+HCD induced NF-κB activation and abolished CIH+HCD induced atherosclerosis. P50 gene deletion inhibited vascular wall inflammation, reduced hepatic TNF-α level, attenuated the elevation in serum cholesterol level and diminished macrophage foam cell formation induced by CIH+HCD exposure. These results demonstrate that inhibition of NF-κB activation abrogates the activation of three major atherogenic mechanisms associated with an abolition of CIH+HCD induced atherosclerosis. NF-κB may be a central common pathway through which CIH+HCD exposure activates multiple atherogenic mechanisms, leading to atherosclerosis.