| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Suppression of atherosclerotic changes in cholesterol-fed rabbits treated with an oral inhibitor of neutral endopeptidase 24.11 (EC 3.4.24.11) Kugiyama, K., S. Sugiyama, et al. (1996), Arterioscler Thromb Vasc Biol 16(8): 1080-7. Abstract: Neutral endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter various functions of cells present in the arterial wall. Recently NEP has been found to exist in the vascular endothelium. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (candoxatril), an orally active NEP inhibitor (NEPI), on the development of atherosclerotic changes in high-cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks as follows: normal rabbit diet (Normal, n = 15), 1.5% cholesterol diet (Cholesterol, n = 15), or 1.5% cholesterol diet containing NEPI (20 mg.kg-1.d-1) (Cholesterol+NEPI, n = 15). At the end of the dietary period, NEPI treatment was found to suppress the surface area of the aorta covered by plaques (% surface area: Cholesterol, 59 +/- 6 versus Cholesterol+NEPI, 36 +/- 7, P <.01) and decreased contents of cholesterol and cholesterol esters in the aortas. NEPI also reduced plasma total cholesterol by 27% of Cholesterol rabbits (1781 +/- 130 mg/dL). The endothelial function, estimated by the endothelium-dependent relaxation of the isolated aortas in response to acetylcholine, was preserved in Cholesterol+NEPI rabbits compared with that in Cholesterol rabbits. NEP enzymatic activities in plasma and the particulate fraction of the homogenates from the aortas in Cholesterol rabbits were both increased, 3.1- and 3.9-fold, respectively, above those in Normal rabbits, but the activities in Cholesterol+NEPI rabbits were significantly lower than those in Cholesterol rabbits. UK73967, an active form of UK79300, or phosphoramidon partly reversed the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings from Cholesterol rabbits in response to exogenous additions of C-type natriuretic peptide (CNP) and substance P, which are NEP substrates known to exist endogenously in the vascular endothelium. The results suggest that the increased NEP activity plays a significant role in atherogenesis, and NEPIs might be therapeutically useful in the prevention of atherosclerosis. Reduction of plasma cholesterol and suppression of degradations in the arteries of endogenously released CNP, substance P, or possibly other kinins known to have anti-atherosclerotic actions may at least partially contribute to the inhibitory effects of NEPIs on atherosclerotic changes. |
| Suppression of bile acid synthesis, but not of hepatic cholesterol 7alpha-hydroxylase expression, by obstructive cholestasis in humans Bertolotti, M., L. Carulli, et al. (2001), Hepatology 34(2): 234-42. Abstract: Regulation of bile acid synthesis, a key determinant of cholesterol homeostasis, is still incompletely understood. To elucidate the feedback control exerted on bile acid biosynthesis in humans with obstructive cholestasis, 16 patients with bile duct obstruction were studied. In vivo 7alpha-hydroxylation, reflecting bile acid synthesis, was assayed in 13 of them by tritium release analysis. Serum 27-hydroxycholesterol was determined by gas chromatography-mass spectrometry. In a subgroup, hepatic cholesterol 7alpha-hydroxylase mRNA was assayed by real-time polymerase chain reaction (PCR), enzyme activity was determined by isotope incorporation, and microsomal cholesterol content was assayed by gas chromatography-mass spectrometry. Age-matched control subjects were studied in parallel. Hydroxylation rates were lower in cholestatic patients (108 +/- 33 mg of cholesterol per day, mean +/- SEM; controls: 297 +/- 40 mg/d; P <.01). The reduction was proportional to the severity of cholestasis, and synthetic rates were normalized in 4 subjects restudied after resolution of biliary obstruction. Consistent findings were obtained by analysis of serum 7alpha-hydroxycholesterol levels. On the other hand, hepatic cholesterol 7alpha-hydroxylase mRNA, microsomal enzyme activity, and cholesterol content tended to be increased in cholestasis. Finally, serum 27-hydroxycholesterol levels were slightly reduced in cholestatic subjects and were not related with the severity of the disease. Suppression of in vivo bile acid synthesis with no corresponding reduction in tissue 7alpha-hydroxylase expression and activity is consistent with nontranscriptional, posttranslational levels of regulation; these may play a role in the feedback control of bile acid synthesis in particular conditions. Alteration of the alternate biosynthetic pathway seems unlikely according to the present data. |
| Suppression of cholesterol 7alpha-hydroxylase transcription and bile acid synthesis by an alpha1-antitrypsin peptide via interaction with alpha1-fetoprotein transcription factor Gerbod-Giannone, M. C., A. Del Castillo-Olivares, et al. (2002), J Biol Chem 277(45): 42973-80. Abstract: alpha1-Antitrypsin (alpha1-AT) is a serum protease inhibitor that is synthesized mainly in the liver, and its rate of synthesis markedly increases in response to inflammation. This increase in alpha1-AT synthesis results in an increase in peptides, like its carboxyl-terminal C-36 peptide (C-36), resulting from alpha1-AT cleavage by proteases. Atherosclerosis is a form of chronic inflammation, and one of the risk factors is elevated plasma cholesterol levels. Because of the correlation between atherosclerosis, plasma cholesterol content, inflammation, and alpha1-AT rate of synthesis, we investigated the effect of the C-36 serpin peptide on hepatic bile acid biosynthesis. We discovered that C-36 is a powerful and specific transcriptional down-regulator of bile acid synthesis in primary rat hepatocytes, through inhibition of the cholesterol 7alpha-hydroxylase/CYP7A1 (7alpha-hydroxylase) promoter. Mice injected with the C-36 peptide also showed a decrease in 7alpha-hydroxylase mRNA. A mutated but very similar peptide did not have any effect on 7alpha-hydroxylase mRNA or its promoter. The sterol 12alpha-hydroxylase/CYP8B1 (12alpha-hydroxylase) promoter is also down-regulated by the C-36 peptide in HepG2 cells but not by the mutated peptide. The DNA element involved in the C-36-mediated regulation of 7alpha- and 12alpha-hydroxylase promoters mapped to the alpha1-fetoprotein transcription factor (FTF) site in both promoters. The C-36 peptide prevented binding of FTF to its target DNA recognition site by direct interaction with FTF. We hypothesize that the C-36 peptide specifically interacts with FTF and induces a conformational change that results in loss of its DNA binding ability, which results in suppression of 7alpha- and 12alpha-hydroxylase transcription. These results suggest that peptides derived from specific serum proteins may alter hepatic gene expression in a highly specific manner. |
| Suppression of established atherosclerosis and xanthomas in mature WHHL rabbits by keeping their serum cholesterol levels extremely low. Effect of pravastatin sodium in combination with cholestyramine Shiomi, M., T. Ito, et al. (1990), Atherosclerosis 83(1): 69-80. Abstract: We investigated the possibility that established atherosclerosis and xanthomas in mature WHHL rabbits could be suppressed or even regressed when their serum cholesterol levels were kept extremely low. Ten-month-old WHHL rabbits were divided into 3 groups, i.e. control rabbits, sacrificed at age 10 months, and placebo and treated rabbits, sacrificed at age 18 months. The treated rabbits were given pravastatin sodium (50 mg/kg/day), an HMG-CoA reductase inhibitor, in combination with cholestyramine (2% in diet), a bile acid sequestrant, for 36 weeks. The serum cholesterol levels and atherogenic lipoproteins in the treated group were markedly reduced, by about 60% (P less than 0.005 and P less than 0.001). Consequently, the degrees of both coronary and aortic atherosclerosis in the treated group were significantly reduced compared with the placebo group, and were almost the same as in the control group. The histopathological findings supported the above results. In addition, the incidence and degree of xanthomas in digital joints in the treated group were significantly reduced. These results suggest that established atherosclerosis and xanthomas in mature WHHL rabbits could be suppressed by keeping their serum cholesterol levels extremely low by the combination drug treatment. |
| Suppression of macrophage eicosanoid synthesis by atherogenic lipoproteins is profoundly affected by cholesterol-fatty acyl esterification and the Niemann-Pick C pathway of lipid trafficking Leventhal, A. R., C. C. Leslie, et al. (2004), J Biol Chem 279(9): 8084-92. Abstract: Atheroma macrophages internalize large quantities of lipoprotein-derived lipids. While most emphasis has been placed on cholesterol, lipoprotein-derived fatty acids may also play important roles in lesional macrophage biology. Little is known, however, about the trafficking or metabolism of these fatty acids. In this study, we first show that the cholesterol-fatty acyl esterification reaction, catalyzed by acyl-CoA:cholesterol acyltransferase (ACAT), competes for the incorporation of lipoprotein-derived fatty acids into cellular phospholipids. Furthermore, conditions that inhibit trafficking of cholesterol from late endosomes/lysosomes to the endoplasmic reticulum (ER), such as the amphipathic amine U18666A and the Npc1+/- mutation, also inhibit incorporation of lipoprotein-derived fatty acids into phospholipids. The biological relevance of these findings was investigated by studying the suppression of agonist-induced prostaglandin E(2) (PGE(2)) and leukotriene C(4)/D(4)/E(4) production during lipoprotein uptake by macrophages, which has been postulated to involve enrichment of cellular phospholipids with non-arachidonic fatty acids (NAAFAs). We found that eicosanoid suppression was markedly enhanced when ACAT was inhibited and prevented when late endosomal/lysosomal lipid trafficking was blocked. Moreover, PGE(2) suppression depended entirely on acetyl-LDL-derived NAAFAs, not on acetyl-LDL-cholesterol, and was not due to decreased cPLA(2) activity per se. These data support the following model: lipoprotein-derived NAAFAs traffic via the NPC1 pathway from late endosomes/lysosomes to a critical pool of phospholipids. In competing reactions, these NAAFAs can be either esterified to cholesterol or incorporated into phospholipids, resulting in suppression of eicosanoid biosynthesis. In view of recent evidence suggesting dysfunctional cholesterol esterification in late lesional macrophages, these data predict that such cells would have highly suppressed eicosanoid synthesis, thus affecting eicosanoid-mediated cell signaling in advanced atherosclerosis. |
| Suppression of neutral cholesterol ester hydrolase activity by antisense DNA of hormone-sensitive lipase Osuga, J., S. Ishibashi, et al. (1997), Biochem Biophys Res Commun 233(3): 655-7. Abstract: In order to investigate the role of the hormone-sensitive lipase (HSL) gene in the activity of neutral cholesterol ester hydrolase (NCEH) from a molecular perspective, Chinese hamster ovary (CHO) cells were transfected with rat antisense hormone-sensitive lipase cDNA, and three different cell lines, designated as anti-HSL, were established. NCEH activity in anti-HSL cells was reduced to approximately 50% of that in control CHO cells. The concentration of cellular esterified cholesterol increased and the concentration of free cholesterol decreased in the anti-HSL cell lines. These results suggest that the HSL gene has a function of NCEH as well. |
| Suppressive effect of simvastatin on intramural small coronary arterial lesions in cholesterol-fed rabbits Kato, H., R. Okada, et al. (1998), Angiology 49(3): 211-20. Abstract: The aim of this study was to examine the suppressive effect of simvastatin on intramural coronary arterial lesions in cholesterol-fed rabbits. In one experiment, six groups of rabbits were fed laboratory chow alone or with added 0.1%, 0.2%, 0.3%, 0.5% or 1.0% cholesterol for 16 weeks. In another experiment, four groups of rabbits were fed a 0.5% cholesterol diet and treated with simvastatin at 1, 3, or 5 mg/kg/day or placebo. In each rabbit, the levels of serum total cholesterol (TC) were determined at 1-week intervals to calculate the integrated values. The lesion induction ratio was defined as the ratio of intramural coronary arteries 50-150 microm in diameter with arterial lipoidosis to the total number of arteries of the same diameter. In the two experiments, there were positive correlations between the lesion induction ratio and integrated TC (r=0.785, P<0.0001 and r=0.763, P<0.0001, respectively). The slopes of the regression lines for integrated TC obtained in the two experiments were similar, but the lesion induction ratio in the simvastatin-treated group was always lower, by about 14%, in comparison with that in the non-simvastatin-treated group. These findings suggest that simvastatin induces lesion reduction not only by reducing the levels of circulating cholesterol but also by directly suppressing the development of lipoidosis. |
| Surface properties of cholesterol-containing membranes detected by Prodan fluorescence Krasnowska, E. K., L. A. Bagatolli, et al. (2001), Biochim Biophys Acta 1511(2): 330-40. Abstract: The fluorescent membrane probe 6-propionyl-2-dimethylaminonaphthalene (Prodan) displays a high sensitivity to the polarity and packing properties of lipid membrane. Contrary to 6-lauroyl-2-dimethylaminonaphthalene (Laurdan), Prodan can also monitor the properties of the membrane surface, i.e., the polar-head pretransition. In bilayers composed of coexisting gel and liquid-crystalline phases, Prodan shows a preferential partitioning in the latter, so that the detected membrane properties mainly belong to fluid domains. In the presence of cholesterol, the packing properties of the gel phase phospholipids are modified in such a way that Prodan can penetrate and label the membrane. Although Prodan labeling of the gel phase is a function of cholesterol concentration, 3 mol percent cholesterol is sufficient for a 60% Prodan labeling with respect to the maximum labeling reached at 15 mol percent cholesterol. We present steady-state and dynamical fluorescence measurements of Prodan in bilayers in the presence of cholesterol. Our results fit the liquid-ordered/liquid-disordered phase model for cholesterol-containing membranes and show that the presence of cholesterol, in addition to modification to the phase state of the hydrophobic portion of the bilayer, strongly affects the packing and the polarity of the membrane hydrophobic-hydrophilic interface. |
| Surface ripples cause the large fluid spaces between gel phase bilayers containing small amounts of cholesterol Simon, S. A. and T. J. McIntosh (1991), Biochim Biophys Acta 1064(1): 69-74. Abstract: Previous studies have found that small concentrations of cholesterol, or several other molecules such as benzene and asialoganglioside, dramatically increase the fluid separation between gel phase phosphatidylcholine bilayers. These observations can not be explained in terms of changes in the repulsive and attractive pressures known to exist between flat gel phase bilayer surfaces. We show here that the increase in fluid space occurs as a consequence of cholesterol inducing large periodic ripples in the plane of the bilayer. The analysis of Mortensen et al. (Biochim. Biophys. Acta 945, 221-245) indicates that the sides of the ripples primarily contain gel phase phosphatidylcholine, whereas the apices are enriched in cholesterol and are liquid-crystalline. We argue that the large fluid spaces can be explained by steric repulsion between adjacent bilayers caused both by thermally induced accordion-like motions of these ripples and defects in the ripple organization. In addition, ripples potentially can decrease van der Waals attraction and change hydration repulsion between bilayers. |
| Surfactant effects of chlorpromazine and imipramine on lipid bilayers containing sphingomyelin and cholesterol Ahyayauch, H., M. A. Requero, et al. (2002), J Colloid Interface Sci 256(2): 284-9. Abstract: The surface-active drugs chlorpromazine (CPZ) and imipramine (IP) have been tested on large unilamellar vesicles composed of phosphatidylcholine (PC), sphingomyelin (SM), and cholesterol (Ch) in different proportions. The well-characterized nonionic detergent Triton X-100 (TX) has also been used in parallel experiments. Leakage of vesicular aqueous contents and bilayer solubilization have been measured for each surfactant molecule and vesicle composition. All three surface-active molecules behave in a qualitatively similar way, irrespective of bilayer composition: they induce leakage at concentrations well below their critical micellar concentrations (cmc) and solubilization near the cmc. In these events, the potency of the three surfactants under study increases with decreasing cmc, in the order IP |
| Surgical intervention in middle-ear cholesterol granuloma Maeta, M., R. Saito, et al. (2003), J Laryngol Otol 117(5): 344-8. Abstract: Eleven patients who had been surgically treated from 1988 to 1999 were retrospectively reviewed in order to evaluate the efficacy of ventilation tube insertion and mastoidectomy with, or without, mastoid obliteration for intractable middle-ear cholesterol granuloma. The mean age registered was 17.2 years at the time of surgical treatment. All cases were unilaterally affected. Five ears were treated with simple mastoidectomy coupled with the insertion of a ventilation tube, while six others had additional mastoid obliteration. The hearing prognosis was excellent with an improved post-operative hearing level of 16.5 dB (cf. pre-operative 37.7 dB). However, morphological prognosis revealed two ears had a residual perforated tympanic membrane without otorrhoea after displacement of the ventilation tube. Of the remaining nine ears with intact placement of the ventilation tube, five had dry ears while four had occasional otorrhoea. Although the morphological prognosis was incomplete, treatments involving at least an insertion of a ventilation tube with thorough mastoidectomy were thought to be necessary. |
| Surgical management of petrous apex cholesterol granulomas Brackmann, D. E. and E. H. Toh (2002), Otol Neurotol 23(4): 529-33. Abstract: OBJECTIVES: To review surgical approaches for drainage of petrous apex cholesterol granulomas, define the criteria for the selection of each approach, and identify factors affecting surgical outcome. STUDY DESIGN: Retrospective chart review and follow-up survey questionnaire. SETTING: Tertiary neurotologic referral center. PATIENTS: Thirty-four patients who underwent surgical treatment for symptomatic cholesterol granulomas of the petrous apex, who had a minimum of 3 months of clinical follow-up care and, in some cases, postoperative radiologic follow-up studies. INTERVENTION: Drainage with or without removal of the cyst lining was achieved through the transcanal infracochlear, transmastoid infralabyrinthine, middle fossa, translabyrinthine, and transotic approaches. Silastic catheters were used to stent drainage sites in some cases. MAIN OUTCOME MEASURES: Relief of symptoms, postoperative cranial nerve function, clinical and radiologic recurrence, and need for further surgical intervention were evaluated. Imaging studies were reviewed to determine how anatomic information influenced surgical decisions and outcome. RESULTS: Clinical improvement of symptoms was observed in 28 patients (82%), and recovery of cranial nerve function was observed in 8 of 9 affected individuals. Serviceable hearing was preserved in all but 1 patient. Five patients required revision surgery for recurrent symptoms and lesions. All 5 patients had undergone drainage procedures without the use of stents. The size of the lesion did not influence the surgical outcome. CONCLUSIONS: Determination of the appropriate surgical approach to the petrous apex is based on hearing status in the affected ear and on the anatomic relationships between the lesion and the surrounding neurovascular structures. The translabyrinthine approach is useful in nonhearing ears. In hearing individuals, anatomy permitting, the transcanal infracochlear approach with stenting is the preferred approach for drainage of petrous apex cholesterol granulomas. |
| Survey of total error of precipitation and homogeneous HDL-cholesterol methods and simultaneous evaluation of lyophilized saccharose-containing candidate reference materials for HDL-cholesterol Cobbaert, C., P. G. Mulder, et al. (1999), Clin Chem 45(3): 360-70. Abstract: BACKGROUND: Standardization of HDL-cholesterol is needed for risk assessment. We assessed for the first time the accuracy of HDL-cholesterol testing in The Netherlands and evaluated 11 candidate reference materials (CRMs). METHODS: The total error (TE) of HDL-cholesterol measurements was assessed in native human sera by 25 Dutch clinical chemistry laboratories. Concomitantly, the suitability of lyophilized, saccharose-containing CRMs (n = 11) for HDL-cholesterol was evaluated. RESULTS: In the precipitation method group, which included 25 laboratories and four methods, the mean (minimum-maximum) TE was 11.5% (2.7-25.2%), signifying that 18 of 25 laboratories satisfied the TE goal of |
| Survival and cardiovascular pathology of heterozygous Watanabe heritable hyperlipidaemic rabbits treated with pravastatin and probucol on a low-cholesterol (0.03%)-enriched diet Brasen, J. H., M. Harsch, et al. (1998), Virchows Arch 432(6): 557-62. Abstract: This study was aimed at determining the effects of a combined pravastatin and probucol regimen on survival and vascular pathology of heterozygous Watanabe heritable hyperlipidaemic (WHHL) rabbits fed a low-cholesterol (0.03%)-enriched diet. Pravastatin monotherapy preceded the combined treatment. In animals receiving pravastatin and the enriched diet (verum group; n = 6), mean total serum cholesterol levels were consistently lowered at a dosage of 5 mg/kg pravastatin and with the combined treatment. Survival was increased (median 45 vs 25 months), while coronary atherosclerosis was less obstructive and altered to a more fibrous type than in controls (n = 8). The extent of aortic lesions, as determined by the relative plaque volume, was not related to survival in either group. However, aortic plaque types in verum group animals revealed less severe stages with a different composition and architecture, with a lower relative content of macrophage-derived foam cells and necrosis and a higher relative content of extracellular matrix. There was also a thicker fibrous cap than in control animals of similar age. Our data reveal a beneficial effect on survival of heterozygous WHHL rabbits when lipid-lowering and antioxidative treatment are combined. This appears to be due both to reduced coronary atherosclerosis and to a different, more stable type of atherosclerotic disease in this animal model. |
| Susceptibility of serum lipids to copper-induced peroxidation correlates with the level of high density lipoprotein cholesterol Shimonov, M., I. Pinchuk, et al. (1999), Lipids 34(3): 255-9. Abstract: As a first step in evaluating the significance of our recently developed method of monitoring the kinetics of copper-induced oxidation in unfractionated serum, we recorded the kinetics of lipid oxidation in the sera of 62 hyperlipidemic patients and analyzed the correlation between oxidation and lipid composition of the sera high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and triglycerides. We used six factors to characterize the kinetics of oxidation, namely, the maximal absorbance of oxidation products (ODmax), the maximal rate of their production (Vmax), and the time at which the rate was maximal (t(max)) at two wavelengths (245 nm, where 7-ketocholesterol and conjugated dienic hydroperoxides absorb intensely, and 268 nm, where the absorbance is mostly due to dienals). The major conclusions of our analyses are that: (i) Both ODmax and Vmax correlate positively with the sum of concentrations of the major oxidizable lipids, cholesterol, and cholesteryl esters. (ii). The value of t(max), which is a measure of the lag preceding oxidation and therefore reflects the resistance of the serum lipids to copper-induced oxidation, exhibits a negative correlation with HDL cholesterol. Although this finding accords with the observation of shorter lags for HDL than for LDL, it is apparently inconsistent with the role of HDL as an antirisk factor in coronary heart diseases. |
| Susceptibility to murine cholesterol gallstone formation is not affected by partial disruption of the HDL receptor SR-BI Wang, D. Q. and M. C. Carey (2002), Biochim Biophys Acta 1583(2): 141-50. Abstract: High density lipoprotein (HDL) promotes reverse cholesterol transport from peripheral tissues to the liver where its cholesterol is secreted preferentially into bile. The scavenger receptor class B type I (SR-BI) is believed to play a pivotal role in unloading HDL cholesterol and its ester to hepatocytes. Here, using male SR-BI "att" mice with a dysfunctional mutation in the Sr-b1 promoter, we studied whether approximately 50% of normal SR-BI expression influences gallstone susceptibility in these mice fed a lithogenic diet containing 1% cholesterol, 0.5% cholic acid and 15% butterfat. Our results showed that the disruption of SR-BI expression reduced cholesterol secretion by 37% in the chow-fed state and 10% on the lithogenic diet, and while delaying incidence slightly, did not influence cumulative susceptibility to cholesterol gallstones. The lithogenic diet induced marked increases in biliary cholesterol and phospholipid secretion rates but not of bile salts. Basal expression of hepatic SR-BI protein was dissimilar in both wild-type and SR-BI mice, and remained unaltered in response to the lithogenic diet. By two independent dual isotope methods, intestinal cholesterol absorption was unimpaired by attenuation of the SR-BI which also displays low-density expression on small intestinal enterocytes. We conclude that although HDL cholesterol is a principal source of biliary cholesterol in the basal state, uptake of cholesterol from chylomicron remnants appears to be the major contributor to biliary cholesterol hypersecretion during diet-induced cholelithogenesis in the mouse. |
| Sustained decreases in weight and serum insulin, glucose, triacylglycerol and cholesterol in JCR:LA-corpulent rats treated with D-fenfluramine Brindley, D. N., P. Hales, et al. (1992), Br J Pharmacol 105(3): 679-85. Abstract: 1. The effects of D-fenfluramine were studied in the JCR:LA-corpulent rat that is grossly obese, hyperphagic, hyperlipidaemic, hyperinsulinaemic and atherosclerosis-prone. 2. Daily doses of 1, 2.5 and 5 mg kg-1 of D-fenfluramine produced sustained decreases in body weight and food intake over a period of 30 days in 6 month old female rats fed ad libitum. This was accompanied by decreases in the circulating concentrations of glucose, triacylglycerol, free cholesterol and insulin. 3. Food restriction imposed by meal feeding also decreased circulating glucose, triacylglycerols, cholesterol and insulin and diminished the effect of D-fenfluramine on these parameters in male and female rats. 4. Addition of D-fenfluramine to drinking water to give a dose of about 0.25 mg kg-1 daily produced a sustained decrease in body weight and food intake of male and female rats over a nine week period. 5. The results show that the JCR:LA-corpulent rat is very sensitive to the pharmacological effects of D-fenfluramine. These rats should provide an appropriate animal model for determining the mechanisms of action of this anti-obesity agent and whether apparently beneficial changes in metabolism translate into long-term protection against premature atherosclerosis. |
| Sustained gallbladder stasis promotes cholesterol gallstone formation in the ground squirrel Xu, Q. W., M. Mantle, et al. (1997), Hepatology 26(4): 831-6. Abstract: Although gallbladder stasis exists in most patients with cholesterol gallstones, it is unknown whether stasis is a causative factor of gallstone disease or merely a consequence of it. We studied the impact of sustained gallbladder stasis induced by a cholecystokinin (CCK)-A receptor antagonist (MK-329) on gallstone formation in ground squirrels fed either a trace or a high-cholesterol diet. MK-329 markedly inhibited gallbladder contraction in vitro in response to CCK (at EC100, control: 3.6 +/- 0.5 vs. MK-329: 1.1 +/- 0.3 g; P <.05) and increased gallbladder fasting volume in vivo (control: 462 +/- 66 vs. MK-329: 1,004 +/- 121 microL; P <.05). Whereas the high-cholesterol diet alone (1%-cholesterol diet + placebo) increased the cholesterol saturation index (CSI) in control animals (trace-cholesterol diet + placebo), MK-329 significantly (P <.05) decreased the CSI in both hepatic and gallbladder bile in animals on the trace-(trace-cholesterol diet + MK-329) as well as on the high-cholesterol diets (1%-cholesterol diet + MK-329). The mucin content of the mucus layer on the epithelial surface of the gallbladder wall more than doubled (P <.05) with the high-cholesterol diet; adding MK-329 to the latter group produced a further 82% increase (P <.05). The cholesterol diet + MK-329 group had the highest (100%) incidence of cholesterol crystals that were evident in fresh gallbladder bile, coincident with a shortened nucleation time (2.5 +/- 0.6 days; P <.05 vs. the cholesterol diet + placebo group, 5.8 +/- 1.0 days or the other 2 groups, >21 days). Bile from animals on the trace-cholesterol diet, whether or not receiving MK-329, lacked crystals in bile and exhibited a normal nucleation time (>21 days). Thus, stasis per se may lower the CSI, but its detrimental effect on the gallbladder predominates locally, and so accelerates cholesterol crystal formation in this model. |
| Sustained reduction in circulating cholesterol in adult hypopituitary patients given low dose titrated growth hormone replacement therapy: a two year study Florakis, D., V. Hung, et al. (2000), Clin Endocrinol (Oxf) 53(4): 453-9. Abstract: OBJECTIVE: To study the effects of short (6 months) and longer-term (up to 24 months) growth hormone (GH) replacement therapy using a dose titration regimen, on lipid and glucose metabolism in GH-deficient, hypopituitary adults. DESIGN: On-going open study of GH treatment up to 24 months. Measurements were performed at baseline and at 6, 12, 18 months and 2 years during therapy (data shown at 6 months and 2 years only). Using a dose titration regimen the median GH dose used to achieve and maintain IGF-I levels above the median, but below the upper limit of the age-related reference range (median IGF-I 202.5 microg/l, range 76-397 microg/l), was 1.2 IU daily (range 0.4-3 IU) 0.8 IU/day, males; 1.6 IU/day, females. PATIENTS: Ninety GH-deficient hypopituitary adults (54 female, median age 48 years, range 19-79 years) entered the study and 24 (14 female, median age 45 years, range 32-79 years) have concluded the 2 year period of assessment. MEASUREMENTS: Body mass index (BMI), waist and hip circumference ratio (WHR), fasting lipids, glucose and glycated haemoglobin (HbA1c) levels were measured at 6 month intervals during GH therapy. RESULTS: Using the dose titration regimen, compared to pretreatment values, total and low density lipoprotein (LDL)-cholesterol levels were significantly lower at 6 months (mean +/- SEM, 5.61+/-0.1 vs. 5.25+/-0.1, and 3.85+/-0.19 vs. 3.43+/-0.26, respectively, P<0.05), and were maintained throughout the study. Male patients had significantly lower pretreatment total and LDL cholesterol levels than females (mean +/- SEM, 5.33+/-0.16 mmol/l vs. 5.7+/-0.12 mmol/l and 3.8+/-0.23 mmol/l vs. 3.92+/-0.29 mmol/l, respectively, P< 0.05). A decrease in total cholesterol was confined to patients with pretreatment total cholesterol levels above 5.8 mmol/l; patients with the highest pretreatment cholesterol levels (> 6.4 mmol/l) obtained the greatest cholesterol reduction (mean +/- SEM, 7.13 +/- 0.14 mmol/l vs. 5.76+/-0.31 mmol/l, P<0.05). A cholesterol-lowering effect of GH therapy was evident in patients who had elevated pre-GH total cholesterol levels even if they were already receiving and continuing lipid lowering medication (mean +/- SEM, 5.62+/-0.22 vs. 5.03+/-0.285, P<0.05). A modest increment in high density lipoprotein (HDL)-cholesterol was evident at 18 months but there was no significant change in triglycerides at any time point. Fasting plasma glucose increased significantly at 6 months but remained within the reference range. Glycated haemoglobin increased significantly at 6 months and was maintained throughout the study; one patient developed frank diabetes mellitus while receiving treatment. There was a weak but significant correlation between the increment in glycated haemoglobin and pretreatment BMI (r = + 0.215, P<0.05). CONCLUSION: The effect of GH on lowering total and low density lipoprotein-cholesterol is more prominent in patients with higher pretreatment cholesterol levels and is evident even in patients receiving other lipid-lowering medication. A modest increment in mean fasting glucose (within the reference range) and mean glycated haemoglobin persisted throughout the study. One patient developed diabetes mellitus. A GH replacement regimen using low dose and careful titration to avoid elevated IGF-I levels and adverse effects is associated with sustained beneficial effects on circulating lipids. |
| Sustained reduction of serum cholesterol in low-dose 6-year simvastatin treatment with minimum side effects in 51,321 Japanese hypercholesterolemic patients Matsuzawa, Y., T. Kita, et al. (2003), Circ J 67(4): 287-94. Abstract: The Japan Lipid Intervention Trial (J-LIT) study, a nationwide cohort study utilizing the clinical practice of general physicians, was designed to clarify the relationship between the incidence of coronary heart disease and serum lipid concentrations during simvastatin therapy, as well as the safety of the therapy, in a large number of Japanese hypercholesterolemic patients. All the enrolled patients were treated with simvastatin. The current study analyzed the lipid lowering effect and safety of the low-dose simvastatin therapy used in the J-LIT study. Open-labeled simvastatin was given to 51,321 patients at an initial dose of mostly 5 mg/day. After 6 months of the treatment, the average serum total cholesterol (TC) and low density lipoprotein-cholesterol concentrations in all the patients followed up were reduced by 18.3% and 26.0%, respectively, and that of high density lipoprotein-cholesterol increased 2.3% on average. These concentrations were well maintained throughout the 6-year treatment period. A minority of patients (1.4%) unexpectedly had a remarkable reduction in TC concentration by more than 40%. Hyper-responders, even to low-dose statin, were found for the first time in this large-scale and long-term investigation. Overall adverse drug reactions occurred in 3.3% of subjects during the 6-year treatment, the major events being hepatic and musculoskeletal disorders, of which the incidence was less than 1%. Low-dose simvastatin therapy of 5 mg/day effectively controlled the serum TC concentration by reducing it by approximately 20% on average in hypercholesterolemic Japanese patients, a reduction that corresponds to the effect of simvastatin 20 mg/day in Western studies. In addition, the low incidence of drug-related adverse events in this study may be also related to the low dosage of simvastatin. |