Distinct mechanisms underlying cholesterol protection against alcohol-induced BK channel inhibition and resulting vasoconstriction

Alcohol (ethanol) at concentrations reached in blood following moderate to heavy drinking (30–80 mM) reduces cerebral artery diameter via inhibition of voltage- and calcium-gated potassium channels of large conductance (BK) in cerebral artery smooth muscle. These channels consist of channel-forming α and regulatory β1 subunits. A high-cholesterol diet protects against ethanol-induced constriction via accumulation of cholesterol within the vasculature. The molecular mechanisms of this protection remain unknown. In the present work, we demonstrate that in vitro cholesterol enrichment of rat middle cerebral arteries significantly increased cholesterol within arterial tissues and blunted constriction by 50 mM of ethanol. Ethanol-induced BK channel inhibition in inside-out patches excised from freshly isolated cerebral artery myocytes was also abolished by cholesterol enrichment. Enrichment of arteries with enantiomeric cholesterol (ent-cholesterol) also blunted BK channel inhibition and cerebral artery constriction in response to ethanol. The similar protection of cholesterol and ent-cholesterol against ethanol action indicates that this protection does not require protein site(s) that specifically sense natural cholesterol. Cholesterol-driven protection against ethanol-induced BK channel inhibition and vasoconstriction was replicated in myocytes and middle cerebral arteries of C57BL/6 mice. BK β1 subunits are known to regulate vascular diameter and its modification by ethanol. However, blunting of an ethanol effect by in vitro cholesterol enrichment was observed in arteries and myocyte membrane patches from BK β1 (KCNMB1) knockout mice. Thus, BK β1 subunits are not needed for cholesterol protection against ethanol effect on BK channel function and cerebral artery diameter.     

Influence of experimental diets on cholesterol and triglyceride levels of rabbit blood serum lipoproteins

Groups of rabbits were fed for six weeks various diets: standard died + ethanol, high-cholesterol diet and a high-cholesterol + ethanol one. During the next six weeks every diet was supplemented with a fresh vegetable (carrot). Cholesterol and triglycerides were determined in the whole serum and in lipoprotein fractions. In rabbits fed standard diet ethanol caused a moderate elevation of VLDL cholesterol and triglyceride and LDL cholesterol levels. In animals on high-cholesterol diet cholesterol and triglyceride concentrations in these fractions were very high. Simultaneous consumption of large amounts of cholesterol and of ethanol resulted in a greater rise of cholesterol concentration in the whole serum and in VLDL and LDL fraction than did high-cholesterol diet alone. Addition of carrot caused a pronounced reduction of serum cholesterol concentration in animals fed all kinds of diets. The reduction concerned mainly VLDL.     

Probiotic Properties of Lactobacillus Strains Isolated from Tibetan Kefir Grains

The objective of this study was to evaluate the functional properties of lactic acid bacteria (LAB) isolated from Tibetan kefir grains. Three Lactobacillus isolates identified as Lactobacillus acidophilus LA15, Lactobacillus plantarum B23 and Lactobacillus kefiri D17 that showed resistance to acid and bile salts were selected for further evaluation of their probiotic properties. The 3 selected strains expressed high in vitro adherence to Caco-2 cells. They were sensitive to gentamicin, erythromycin and chloramphenicol and resistant to vancomycin with MIC values of 26 µg/ml. All 3 strains showed potential bile salt hydrolase (BSH) activity, cholesterol assimilation and cholesterol co-precipitation ability. Additionally, the potential effect of these strains on plasma cholesterol levels was evaluated in Sprague-Dawley (SD) rats. Rats in 4 treatment groups were fed the following experimental diets for 4 weeks: a high-cholesterol diet, a high-cholesterol diet plus LA15, a high-cholesterol diet plus B23 or a high-cholesterol diet plus D17. The total cholesterol, triglyceride and low-density lipoprotein cholesterol levels in the serum were significantly (P<0.05) decreased in the LAB-treated rats compared with rats fed a high-cholesterol diet without LAB supplementation. The high-density lipoprotein cholesterol levels in groups B23 and D17 were significantly (P<0.05) higher than those in the control and LA15 groups. Additionally, both fecal cholesterol and bile acid levels were significantly (P<0.05) increased after LAB administration. Fecal lactobacilli counts were significantly (P<0.05) higher in the LAB treatment groups than in the control groups. Furthermore, the 3 strains were detected in the rat small intestine, colon and feces during the feeding trial. The bacteria levels remained high even after the LAB administration had been stopped for 2 weeks. These results suggest that these strains may be used in the future as probiotic starter cultures for manufacturing novel fermented foods.     

Dietary cholesterol is essential to mast cell activation and associated obesity and diabetes in mice

Mast cell (MC) deficiency in Kit^W-sh/W-sh mice and inhibition with disodium chromoglycate (DSCG) or ketotifen reduced obesity and diabetes in mice on a high-cholesterol (1.25%) Western diet. Yet, Kit-independent MC-deficient mice and mice treated with DSCG disproved MC function in obesity and diabetes when mice are fed a high-fat diet (HFD) that contains no cholesterol. This study reproduced the obesity and diabetes inhibitory activities of DSCG and ketotifen from mice on a Western diet. Yet, such inhibitory effects were diminished in mice on the HFD. DSCG and ketotifen MC inhibitory activities were recovered from mice on the HFD supplemented with the same amount of cholesterol (1.25%) as that in the Western diet. DSCG and ketotifen effectively blunted the high-cholesterol diet-induced elevations of blood histamine and adipose tissue MC degranulation. Pearson's correlation test demonstrated significant and positive correlations between plasma histamine and total cholesterol or low-density lipoprotein-cholesterol (LDL). In cultured bone marrow-derived MCs, plasma from mice following a Western diet or a cholesterol-supplemented HFD, but not those from HFD-fed mice, induced MC degranulation and the release of β-hexosaminidase, histamine, and serotonin. IgE, LDL, very low-density lipoprotein, and high-density lipoprotein also induced MC activation, which can be inhibited by DSCG and ketotifen depending on the doses and types of MC inhibitors and cholesterol, and also the MC granule molecules of interest. DSCG or ketotifen lost their activities in inhibiting LDL-induced activation of MCs from LDL receptor-deficient mice. These results indicate that dietary cholesterol critically influences the function of mouse MCs.     

Increase of bile acids synthesis and excretion caused by taurine administration prevents the ovariectomy-induced increase in cholesterol concentrations in the serum low-density lipoprotein fraction of Wistar rats

We examined the effect of dietary taurine on the concentrations of serum cholesterol and apolipoprotein in lipoprotein fractions of Six-month-old ovariectomized, which were used as a model of hypercholesterolemia in postmenopausal woman, or sham operated rats. Taurine significantly reduced the serum total and low-density lipoprotein cholesterol concentrations only in the ovariectomized rats. In contrast, taurine significantly lowered the serum apolipoprotein B concentration and serum very low-density lipoprotein-apolipoprotein E concentration only in the sham operated rats. The serum total and high density lipoprotein-apolipoprotein E concentrations were significantly lower in the rats fed taurine than in those fed the control diet regardless of whether they had undergone ovariectomy. The esterified cholesterol level in the liver was significantly lower and the level of hepatic cholesterol 7 alpha-hydroxylase activity was significantly higher in the rats fed taurine than in those fed the control diet. The total bile acids concentration in the feces and intestinal contents of rats fed taurine were significantly higher than those in rats fed the control diet regardless of whether they had undergone ovariectomy. In the sham-rats, taurine accelerated bile acid synthesis and excretion, thereby increasing cholesterol consumption. The increased cholesterol consumption might be compensated by accelerating cholesterol synthesis and/or reducing the synthesis and release of very low-density lipoprotein from the liver. But in the ovariectomized rats, although taurine also accelerated bile acid synthesis and excretion, cholesterol demand might be compensated by excess cholesterol in the blood.     

Enteric lactoferrin attenuates the development of high-fat and high-cholesterol diet-induced hypercholesterolemia and atherosclerosis in Microminipigs

Previously, we found that enteric lactoferrin (eLF) could reduce the visceral fat accumulation known to associate strongly with metabolic syndrome symptoms and consequently with an increased risk of atherosclerosis. In this study, the atherosclerosis-preventive potential of LF was assessed in a high-fat and high-cholesterol diet (HFCD)-induced hypercholesterolemia and atherosclerosis model using Microminipig?. Eight-week orally administered eLF remarkably reduced the HFCD-induced serum total and low-density lipoprotein cholesterol levels but not high-density lipoprotein cholesterol levels. A histological analysis of 15 arteries revealed that eLF systemically inhibited the development of atherosclerotic lesions. Pathway analysis using identified genes that characterized eLF administration in liver revealed significant changes in the steroid biosynthesis pathway (ssc00100) and all affected genes in this pathway were upregulated, suggesting that cholesterol synthesis inhibited by HFCD was recovered by eLF. In summary, eLF could potentially prevent the hypercholesterolemia and atherosclerosis through protecting homeostasis from HFCD-induced dysfunction of cholesterol metabolism.     

Regulation of hepatic very-low-density lipoprotein secretion in rats fed on a diet high in unsaturated fat.

Rats were fed ad libitum on either a standard, high-carbohydrate, chow diet or a similar diet supplemented with 15% unsaturated fat (corn oil). Hepatocytes were prepared either during the dark phase (D6-hepatocytes) or during the light phase (L2-hepatocytes) of the diurnal cycle. In hepatocytes from rats fed on the unsaturated-fat-containing diet, secretion of very-low-density lipoprotein (VLDL) triacylglycerol was inhibited to a greater extent in the D6- than in the L2-hepatocytes. Plasma non-esterified fatty acid concentrations were elevated to the same extent at both D6 and L2 in the unsaturated-fat-fed animals. The secretion of VLDL esterified and non-esterified cholesterol was relatively insensitive to changes in the unsaturated-fat content of the diet. This resulted in proportionate increases in the content of these lipid constituents compared with that of triacylglycerol in the nascent VLDL. There was also an increase in the ratio of esterified to non-esterified cholesterol in the nascent VLDL produced by hepatocytes of the unsaturated-fat-fed animals. In the D6-hepatocytes from the unsaturated-fat-fed animals, the decrease in the secretion of VLDL triacylglycerol could not be reversed by addition of exogenous oleate (0.7 mM) to the incubation medium. In contrast, addition of a mixture of lactate (10 mM) and pyruvate (1 mM) stimulated both fatty acid synthesis de novo and the rate of VLDL triacylglycerol secretion. Secretion of esterified and non-esterified cholesterol also increased under these conditions. Insulin suppressed the secretion of VLDL triacylglycerol and cholesteryl ester under a wide range of conditions in all types of hepatocyte preparations. Non-esterified cholesterol secretion was unaffected. In hepatocytes prepared from the fat-fed animals, these effects of insulin were more pronounced at D6 than at L2. Glucagon also inhibited VLDL lipid secretion in all types of hepatocyte preparations. The decrease in cholesterol secretion was due equally to decreases in the rates of secretion of both esterified and non-esterified cholesterol.     

The compartmentation of non-esterified and esterified cholesterol in the superovulated rat ovary

1. The specific radioactivities of non-esterified and esterified cholesterol, progesterone and 20alpha-hydroxypregn-4-en-3-one were determined in slices of superovulated rat ovary after incubation with [1-(14)C]acetate in vitro for various times. The specific radioactivities of progesterone and 20alpha-hydroxypregn-4-en-3-one were equal, and (during the fourth hour of incubation) exceeded those of the non-esterified cholesterol and the esterified cholesterol by factors of 2.8 and 7.6 respectively. 2. After separation of homogenates of superovulated rat ovary slices previously incubated with [(14)C]acetate into subcellular fractions by differential centrifugation, the specific radioactivities of non-esterified cholesterol in the cytosol, mitochondria, lipid-containing storage granules and microsomal fraction were 1220, 1510, 1420 and 4020d.p.m./mumol respectively; the corresponding values for the specific radioactivity of the esterified cholesterol were 600, 700, 730 and 760d.p.m./mumol. The specific radioactivities of progesterone and 20alpha-hydroxypregn-4-en-3-one were equal in all fractions; the corresponding mean specific radioactivity of progesterone+20alpha-hydroxypregn-4-en-3-one was 6150d.p.m./mumol. 3. By using glutamate dehydrogenase and cytochrome (a+a(3)) as mitochondrial markers, the presence of cholesterol side-chain cleavage enzyme was demonstrated in microsomal fraction free of mitochondrial contamination. 4. The specific radioactivities of ovarian non-esterified and esterified cholesterol, progesterone and 20alpha-hydroxypregn-4-en-3-one were determined up to 8h after the intravenous injection of [4-(14)C]cholesterol into superovulated rats. At all times the specific radioactivities of progesterone and 20alpha-hydroxypregn-4-en-3-one were equal to the specific radioactivity of non-esterified cholesterol and exceeded, by up to 3.3-fold, that of the esterified cholesterol. 5. It is concluded that non-esterified cholesterol formed from [(14)C]acetate in the endoplasmic reticulum equilibrates slowly with non-esterified cholesterol in other subcellular fractions, and is preferentially converted into steroids. Such a mechanism presupposes the operation of a microsomal cholesterol side-chain cleavage enzyme using non-esterified cholesterol as its substrate. Unrelated evidence is presented in support of the existence of such an enzyme. The results are discussed in the light of other biochemical and electron-microscopic findings relating to the compartmentation of cholesterol in steroidogenic tissues.     

Fluorescent lipoprotein probe

The fluorescent cholesterol analog cholesta-5,7,9(11)triene-3-β-ol was used to label high-density and low-density lipoproteins in vivo (rabbit) and in vitro (human). Rabbit feeding experiments demonstrated that in vivo both the esterified and nonesterified forms of the fluorophore were incorporated by these particles. Using in vitro labeling techniques, it was possible to selectively incorporate either the free form of the fluorophore or both the free and the esterified forms depending upon the presence or absence of serum esterases during incubation. Subsequent to labeling, the thermotropic behavior of the low- and high-density lipoproteins was evaluated using temperature-dependent fluorescence intensity measurements. Purified low-density lipoprotein samples (human and rabbit) containing both forms of the fluorophore were observed to undergo a thermotropic transition between 27 and 32°C. However, this transition was not observed in low-density lipoprotein samples containing only the nonesterified form of the probe nor was it observed in any of the high-density lipoprotein samples, even those containing both forms of the fluorophore. These results provide further evidence that the previously reported thermotropic transition in low-density lipoprotein is due to a reordering of the low-density lipoprotein cholesterol ester core (Deckelbaum, R.J., Shipley, G. G., Small, D. M., Lees, R. S., and George, P. K. (1975) Science190, 392–394; Sears, B., Deckelbaum, R. J., Janiak, M. J., Shipley, G. G., and Small, D. M. (1976) Biochemistry15, 4151–4157; Chana, G. S., Sheppard, R. J., Mills, G. L., and Grant, E. H. (1980) Phys. Med. Biol.25, 427–432).     

High-cholesterol diet-induced lipoproteins stimulate lipoprotein lipase secretion in cultured rat alveolar macrophages

We have previously shown that cultured rat alveolar macrophages synthesize and secrete lipoprotein lipase into the medium. The purpose of the present experiments is to examine whether cholesterol-enriched lipoproteins from cholesterol-fed animals have any effects on the lipoprotein lipase secretion and the lipid accumulation in macrophages. Macrophages incubated with the VLDL obtained from rats fed a normal diet secreted 2-fold higher amounts of lipoprotein lipase than those without lipoproteins. Intermediate-, low- and very-low-density lipoproteins from rats fed a high-cholesterol diet also enhanced the lipoprotein lipase secretion. Normal high- and low-density lipoproteins, and high-density lipoproteins from hypercholesterolemic animals did not cause any increase in the lipoprotein lipase secretion. The lipoproteins which stimulated the lipoprotein lipase secretion caused intracellular accumulation of both triacylglycerol and cholesterol. It is speculated that macrophages residing in the environment rich in lipoproteins, especially hypercholesterolemic lipoproteins, take them up and accumulate lipids intracellularly, and that this process links with the lipoprotein lipase secretion. The secreted lipoprotein lipase could facilitate, by degrading lipoproteins, the uptake of lipoprotein lipase-modified lipoproteins. Probably such a series of events is of importance in the foam cell formation of macrophages.     

The metabolism of esterified cholesterol in rabbit plasma low density lipoproteins

The metabolism of esterified cholesterol in plasma low density lipoproteins (LDL) has been studied in rabbits. LDL labelled with ³H in the esterified and free cholesterol moieties was isolated from the serum of donar rabbits which has been injected with [³H]mevalonic acid, and subsequently either incubated at 37°C in vitro with unlabelled rabbit serum or unlabelled rabbit lipoprotein fractions, or reinjected into other rabbits.In vitro there was found to be a transfer of 40–60% of the esterified [³H]-cholesterol out of LDL into both the very low density lipoprotein (VLDL) and high density lipoprotein (HDL) fractions which could not be explained in terms of net transfer of esterified cholesterol mass. In the incubations of labelled LDL with either of the other unlabelled lipoprotein fractions, transfers were apparent only if the dialysed 1.21 g/ml infranatant of rabbit serum was also present. The transfer of esterified [³H]cholesterol out of LDL was enhanced when lecithin:cholesterol acyltransferase was active.After reinjecting labelled LDL into other rabbits, it was found that more than half of the esterified [³H]cholesterol removed from the recipient LDL fraction during the first 30 min was not lost from the plasma compartment, but rather was recovered in HDL. There was only minimal in vivo transfer of LDL esterified [³H]cholesterol into VLDL.It has been concluded that in vitro the esterified cholesterol in LDL exchanges with that in both the VLDL and HDL, and that in vivo the esterified cholesterol pools in LDL and HDL may represent parts of a progressively equilibrating plasma pool.     

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.     

A high-fat diet and high-fat and high-cholesterol diet may affect glucose and lipid metabolism differentially through gut microbiota in mice

This study was conducted to investigate the effects of a high-fat diet (HFD) and high-fat and high-cholesterol diet (HFHCD) on glucose and lipid metabolism and on the intestinal microbiota of the host animal. A total of 30 four-week-old female C57BL/6 mice were randomly divided into three groups (n=10) and fed with a normal diet (ND), HFD, or HFHCD for 12 weeks, respectively. The HFD significantly increased body weight and visceral adipose accumulation and partly lowered oral glucose tolerance compared with the ND and HFHCD. The HFHCD increased liver weight, liver fat infiltration, liver triglycerides, and liver total cholesterol compared with the ND and HFD. Moreover, it increased serum high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol compared with the ND and HFD and upregulated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase significantly. The HFHCD also significantly decreased the α-diversity of the fecal bacteria of the mice, to a greater extent than the HFD. The composition of fecal bacteria among the three groups was apparently different. Compared with the HFHCD-fed mice, the HFD-fed mice had more Oscillospira, Odoribacter, Bacteroides, and [Prevotella], but less [Ruminococcus] and Akkermansia. Cecal short-chain fatty acids were significantly decreased after the mice were fed the HFD or HFHCD for 12 weeks. Our findings indicate that an HFD and HFHCD can alter the glucose and lipid metabolism of the host animal differentially; modifications of intestinal microbiota and their metabolites may be an important underlying mechanism.     

Effect of seaweed mixture intake on plasma lipid and antioxidant profile of hyperholesterolaemic rats

Cardiovascular disease (CVD) is the leading cause of death in many countries. Hypercholesterolaemia is a recurring risk factor in CVD leading to coronary atherosclerosis, stroke and ischemic heart disease. Previous research has proven that seaweeds are highly nutritious, providing a good source of dietary fibre, minerals, proteins and vitamins as well as being high in antioxidants. Antioxidants have been known to retard low-density lipoprotein (LDL) oxidation to reduce CVD risk in hypercholesterolaemia. However, there is yet to be a study on the effect of a mixture of different seaweed species on cholesterol lowering properties. Therefore, this study was designed to investigate the effects of a mixture of extracts from two seaweed species, red seaweed Kappaphycus alvarezii and brown seaweed Sargassum polycystum on plasma lipid and antioxidant profiles of rats fed high-cholesterol diet. S. polycystum extract significantly decreased plasma cholesterol by 37.52 % over an 8-week treatment period compared to K. alvarezii and mixture groups. However, S. polycystum showed an increase in plasma triglyceride (TG) levels by 16.66 %. K. alvarezii extract most effectively decreased TG levels by 40.11 % and the mixture extract most effectively increased high-density lipoprotein cholesterol by 56.71 %. All treatment groups were able to reduce LDL cholesterol levels compared to the high-cholesterol group, with no significant differences between them. K. alvarezii and S. polycystum mixture extract had the best atherogenic index, which is an indicator of lipid disorder in coronary diseases, among treatment and high-cholesterol-fed groups. All treatment groups were able to restore enzyme antioxidant levels (superoxide dismutase and catalase) to normal.     

Selective cholesterol dynamics between lipoproteins and caveolae/lipid rafts

Although low-density lipoprotein (LDL) receptor-mediated cholesterol uptake through clathrin-coated pits is now well understood, the molecular details and organizing principles for selective cholesterol uptake/efflux (reverse cholesterol transport, RCT) from peripheral cells remain to be resolved. It is not yet completely clear whether RCT between serum lipoproteins and the plasma membrane occurs primarily through lipid rafts/caveolae or from non-raft domains. To begin to address these issues, lipid raft/caveolae-, caveolae-, and non-raft-enriched fractions were resolved from purified plasma membranes isolated from L-cell fibroblasts and MDCK cells by detergent-free affinity chromatography and compared with detergent-resistant membranes isolated from the same cells. Fluorescent sterol exchange assays between lipoproteins (VLDL, LDL, HDL, apoA1) and these enriched domains provided new insights into supporting the role of lipid rafts/caveolae and caveolae in plasma membrane/lipoprotein cholesterol dynamics: (i) lipids known to be translocated through caveolae were detected (cholesteryl ester, triacylglycerol) and/or enriched (cholesterol, phospholipid) in lipid raft/caveolae fractions; (ii) lipoprotein-mediated sterol uptake/efflux from lipid rafts/caveolae and caveolae was rapid and lipoprotein specific, whereas that from non-rafts was very slow and independent of lipoprotein class; and (iii) the rate and lipoprotein specificity of sterol efflux from lipid rafts/caveolae or caveolae to lipoprotein acceptors in vitro was slower and differed in specificity from that in intact cells-consistent with intracellular factors contributing significantly to cholesterol dynamics between the plasma membrane and lipoproteins.     

Urotensin II Promotes Atherosclerosis in Cholesterol-Fed Rabbits

Urotensin II (UII) is a vasoactive peptide composed of 11 amino acids that has been implicated to contribute to the development of cardiovascular disease. The purpose of this study was to investigate whether UII affects the development of atherosclerosis in cholesterol-fed rabbits. UII was infused for 16 weeks through an osmotic mini-pump into male Japanese White rabbits fed on a high-cholesterol diet. Plasma lipids and body weight were measured every 4 weeks. Aortic atherosclerotic lesions along with cellular components, collagen fibers, matrix metalloproteinase-1 and -9 were examined. Moreover, vulnerability index of atherosclerotic plaques was evaluated. UII infusion significantly increased atherosclerotic lesions within the entire aorta by 21% over the control (P = 0.013). Atherosclerotic lesions were increased by 24% in the aortic arch (P = 0.005), 11% in the thoracic aorta (P = 0.054) and 18% in the abdominal aorta (P = 0.035). These increases occurred without changes in plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides or body weight. Immunohistochemical staining revealed that macrophages and matrix metalloproteinase-9 were significantly enhanced by 2.2-fold and 1.6-fold in UII group. In vitro studies demonstrated that UII up-regulated the expression of vascular cell adhesion protein-1 and intercellular adhesion molecule-1 in human umbilical vein endothelial cells, which was inhibited by the UII receptor antagonist urantide. In conclusion, our results showed that UII promotes the development of atherosclerotic lesions and destabilizes atherosclerotic plaques in cholesterol-fed rabbits.     

Phospholipid transfer protein deficiency ameliorates diet-induced hypercholesterolemia and inflammation in mice

Phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids from triglyceride-rich lipoproteins into HDL. PLTP has been shown to be an important factor in lipoprotein metabolism and atherogenesis. Here, we report that chronic high-fat, high-cholesterol diet feeding markedly increased plasma cholesterol levels in C57BL/6 mice. PLTP deficiency attenuated diet-induced hypercholesterolemia by dramatically reducing apolipoprotein E-rich lipoproteins (-88%) and, to a lesser extent, LDL (-40%) and HDL (-35%). Increased biliary cholesterol secretion, indicated by increased hepatic ABCG5/ABCG8 gene expression, and decreased intestinal cholesterol absorption may contribute to the lower plasma cholesterol in PLTP-deficient mice. The expression of proinflammatory genes (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) is reduced in aorta of PLTP knockout mice compared with wild-type mice fed either a chow or a high-cholesterol diet. Furthermore, plasma interleukin-6 levels are significantly lower in PLTP-deficient mice, indicating reduced systemic inflammation. These data suggest that PLTP appears to play a proatherogenic role in diet-induced hyperlipidemic mice.     

Maternal lipid metabolism and placental lipid transfer

During early pregnancy, long-chain polyunsaturated fatty acids (LC-PUFA) may accumulate in maternal fat depots and become available for placental transfer during late pregnancy, when the fetal growth rate is maximal and fetal requirements for LC-PUFAs are greatly enhanced. During this late part of gestation, enhanced lipolytic activity in adipose tissue contributes to the development of maternal hyperlipidaemia; there is an increase in plasma triacylglycerol concentrations, with smaller rises in phospholipid and cholesterol concentrations. Besides the increase in plasma very-low-density lipoprotein, there is a proportional enrichment of triacylglycerols in both low-density lipoproteins and high-density lipoproteins. These lipoproteins transport LC-PUFA in the maternal circulation. The presence of lipoprotein receptors in the placenta allows their placental uptake, where they are hydrolysed by lipoprotein lipase, phospholipase A(2) and intracellular lipase. The fatty acids that are released can be metabolized and diffuse into the fetal plasma. Although present in smaller proportions, maternal plasma non-esterified fatty acids are also a source of LC-PUFA for the fetus, their placental transfer being facilitated by the presence of a membrane fatty acid-binding protein. There is very little placental transfer of glycerol, whereas the transfer of ketone bodies may become quantitatively important under conditions of maternal hyperketonaemia, such as during fasting, a high-fat diet or diabetes. The demands for cholesterol in the fetus are high, but whereas maternal cholesterol substantially contributes to fetal cholesterol during early pregnancy, fetal cholesterol biosynthesis rather than cholesterol transfer from maternal lipoproteins seems to be the main mechanism for satisfying fetal requirements during late pregnancy.     

Improving effect of dietary taurine supplementation on the oxidative stress and lipid levels in the plasma,liver and aorta of rabbits fed on a high-cholesterol diet

The effect of a high-cholesterol diet with or without taurine on lipids and oxidative stress in the plasma, liver and aorta of rabbits was investigated. The animals were maintained on a basal diet (control), a high-cholesterol diet (HC, 1% w/w), or a high- cholesterol diet supplemented with taurine (HCHT, 2.5% w/w) for two months. Taurine has an ameliorating effect on atherosclerosis together with a decreasing effect on the cholesterol and triglyceride levels in rabbits fed on an HC diet. The HCHT diet caused a significant decrease in the malondialdehyde (MDA) and diene conjugate (DC) levels in the plasma, liver and aorta of rabbits as compared to the HC group. This treatment did not alter the antioxidant system in the liver of rabbits in the HC group. Our findings indicate that taurine ameliorated oxidative stress and cholesterol accumulation in the aorta of rabbits fed on the HC diet and that this effect may be related to its antioxidative potential as well as its reducing effect on serum lipids.     

下丘脑Orexin 对肥胖大鼠能量代谢的影响

目的:探讨下丘脑注射OXR-1选择性受体拮抗剂ACT-335827对肥胖大鼠代谢的效果。方法:通过高脂饮食建立肥胖大鼠模型,采用CODA 8通道高通量非侵入性血压系统(EMKA)测量血压;所有脂类都使用商品酶试剂盒和TOSHIBA-40FR全自动分析仪测量;空腹血糖采用葡萄糖氧化酶法;空腹胰岛素采用放射免疫法测定。肥胖大鼠出现代谢紊乱后,给予ACT-335827处理,检测大鼠体重、血压、脂肪、甘油三酯、总胆固醇、高密度脂蛋白、低密度脂蛋白、游离脂肪酸(NEFA)、瘦素、空腹血糖及空腹胰岛素等的变化。结果:与普通饮食组相比,经过10周高脂饮食,高脂饮食组大鼠体重显著升高(P0.05),给予ACT-335827处理后,普通大鼠的体重、血压、脂肪含量、脂代谢等均无明显变化;与高脂饮食和高脂饮食加生理盐水处理组大鼠比较,高脂饮食加ACT-335827处理组肥胖大鼠的体重显著下降(P0.05),腹部和附睾脂肪含量下降(P0.05),低密度脂蛋白、甘油三酯、总胆固醇、瘦素水平下降(P0.05),空腹血糖及空腹胰岛素也显著降低(P0.05),但血压、肠系膜脂肪和肩胛棕色脂肪、高密度脂蛋白和NEFA无明显变化(P0.05)。结论:ACT-335827对肥胖大鼠的代谢紊乱具有改善作用,对肥胖大鼠有一定的减肥作用。