共查询到20条相似文献,搜索用时 46 毫秒
1.
Chronic lymphocytic leukemia (CLL) cells express lower low density lipoprotein (LDL) receptor activity and higher 3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA) reductase activity than normal mononuclear blood cells indicating that CLL cells may depend on cholesterol synthesis
for their proliferation. We studied the effects of competitive inhibitors of HMG-CoA reductase on malignant lymphocyte proliferation
in vitro and in vivo. Tumor B-cells from 13 patients with CLL, hairy cell leukemia, or immunoblastic B-cell lymphoma were cultured for 4 d in
the presence of B-cell mitogens and cholesterol synthesis inhibitors. Simvastatin and lovastatin suppressed, in a concentration-dependent
manner, the mitogen-induced cellular thymidin uptake in medium with 10% human AB-serum or lipoprotein-deficient serum. Pravastatin
was active only in medium with lipoprotein-deficient serum. Ten previously untrated patients with CLL received simvastatin
orally, 40 mg daily for 12 wk. Mean reductions in total plasma and LDL cholesterol were 30% (range 9–46%) and 37% (range 16–63%),
respectively. Cells from four patients showed moderate to minor increases in the degradation rate of 125I-LDL suggesting that the need for exogenous cholesterol had increased, three patients showed an increase in HMG-CoA reductase
activity, and the cells from one patient showed both. There was no significant change in the clinical disease status during
medication. However, four of the ten patients developed a therapy-demanding progressive disease during the subsequent year.
Further clinical studies with cholesterol synthesis inhibitors in leukemia are warranted. 相似文献
2.
In this communication we attempt to provide one possible explanation for the observed differences regarding kinetics and distribution
between simvastatin and pravastatin. Rats treated with simvastatin or pravastatin exhibited a reduction in the incorporation
of [2-14C]acetate into liver cholesterol and displayed lower plasma mevalonate levels as compared to control animals. Moreover, both
the total and dephosphorylated 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34) activities, particularly 1
h after treatment, were greatly reduced in liver microsomes obtained from simvastatin-treated as compared to control rats.
During the same time frame, these parameters were actually elevated with pravastatin treatment. It is known that HMG-CoA reductase
synthesis and activity increase following their competitive inhibition. Our results suggest that pravastatin, at 1 h following
treatment, was no longer bound to the enzyme; however, it had entered the liver because its inhibitory effect on cholesterol
synthesis was manifest at early times after administration. These data provide a plausible rationale for the earlier observation
that activity of simvastatin persists longer in plasma than does that of pravastatin. 相似文献
3.
Thein vitro andin vivo effects of lovastatin on fatty acid metabolism were studied in isolated rat hepatocytes. When addedin vitro to cell incubations, lovastatin stimulatedde novo fatty acid synthesis and acetyl-CoA carboxylase activity, whereas fatty acid synthase, activity was unaffected. Lovastatin
depressed palmitate, but not octanoate, oxidation. This may be attributed to the lovastatin-induced increase, in intracellular
malonyl-CoA levels, as no concomitant changes of carnitine palmitoyltransferase I (CPT-I) specific activity was detected.
Lovastatin had no effect on the synthesis and secretion of triacylglycerols and phospholipids in the form of very low density
lipoproteins (VLDL). When rats were fed a diet supplemented with 0.1% (w/w) lovastatin for one week, both acetyl-CoA carboxylase
activity andde novo fatty acid synthesis were reduced compared to pair-fed controls, whereas fatty acid synthase activity was unaffected. Palmitate
oxidation was enhanced in the lovastatin-fed group. There was an increase in CPT-I activity but no change in intracellular
concentration of malonyl-CoA. Lovastatin feeding and no significant effect either on the esterification of exogenous palmitic
acid into both cellular and VLDL triacylglycerols and phospholipids or on hepatic lipid accumulation. Thein vitro andin vivo effects of lovastatin were not significantly different between periportal and perivenous hepatocytes. The results indicate
that: (i) the administration of lovastatin increased the fatty acid-oxidative capacity of the liver at the expense of its
lipogenic capacity, (ii) the rate ofde novo cholesterol synthesis did not seem to be a limiting factor in the synthesis and secretion of VLDL and (iii) lovastatin produced
opposite effects on hepatic fatty acid metabolismin vitro andin vivo. 相似文献
4.
The effects of atorvastatin and simvastatin on hydroxy methylglutary (HMG)-CoA reductase activity and mRNA abundance were
studied in guinea pigs randomized to three groups: untreated animals and those treated with 20 mg/kg of atorvastatin or simvastatin.
Guinea pigs were fasted for 0, 6, 12, or 18 h in an attempt to remove the drug from their systems. Reductase activity and
mRNA levels were analyzed after each time point. Reductase inhibitor treatment resulted in 50–60% lower cholesterol concentrations
compared to untreated guinea pigs (P<0.0001), while plasma triacylglycerol (TAG) concentrations did not differ among groups. Plasma cholesterol and TAG were 50–70%
lower after 18 h fasting in the three groups (P<0.001). In the nonfasting state, simvastatin and atorvastatin treatment did not affect HMG-CoA reductase activity compared
with untreated animals. However, after 6 h of fasting, simvastatin-treated guinea pigs had higher HMG-CoA reductase activity
than untreated animals (P<0.01), suggesting that the drug had been removed from the enzyme. In contrast, atorvastatin-treated guinea pigs maintained
low enzyme activity even after 18 h of fasting. Further, HMG-CoA reductase mRNA abundance was increased by sevenfold after
atorvastatin treatment and by twofold after simvastatin treatment (P<0.01). These results suggest that sinvastatin and atorvastatin
have different half-lives, which may affect HMG-CoA reductase mRNA levels. The increase in reductase activity by simvastatin
during fasting could be related to an effect of this statin in stabilizing the enzyme. In contrast, atorvastatin, possibly
due to its longer half-life, prolonged inhibition of HMG-CoA reductase activity and resulted in a greater increase in mRNA
synthesis. 相似文献
5.
Ri-T-DNA-transformed carrot roots were used for investigating sterol metabolism by the arbuscular mycorrhizal (AM) fungus
Glomus intraradices under three distinct experimental conditions: (i) a symbiotic stage (fungus still attached to the host roots); (ii) a detached
stage (fungus physically separated from the roots); and (iii) a germinating stage (germinating spores). In all three stages,
G. intraradices was found to contain a mixture of 24-alkylated sterols, with 24-methyl and 24-ethyl cholesterol as the main compounds, but
no ergosterol, the predominant sterol in most fungi. Feeding experiments with [1-14C]sodium acetate were performed to check the ability of the fungus to synthesize sterols. Whatever the experimental conditions,
G. intraradices was able to actively take up exogenous acetate and to incorporate it into sterols and their precursors. Our data provide
first evidence for de novo sterol synthesis by an AM fungus. 相似文献
6.
Statins are commonly prescribed antilipidemic and anticholesterol class of drugs. In addition to their major role, they have been found to have anticancer effects on in vitro, animal and clinical studies. The aim of this study was to investigate the effects of six different statins (rosuvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, and atorvastatin) on A549 cancer cells lipids by Fourier transform infrared (FTIR) spectroscopy. Proliferation tests were carried out to detect the half-maximal inhibitory concentrations (IC50) of each statin on A549 cells. The IC50 values were 50 μM for simvastatin, 150 μM for atorvastatin and pravastatin, and 170 μM for fluvastatin, 200 μM for rosuvastatin and lovastatin on A549 cells. No correlation was found between the antiproliferative effects of the statins and lipid-lowering effect. The cells were treated with IC5, IC10, and IC50 values of each statins concentration and lipid extracts were compared using FTIR spectroscopy. The results indicated that different statins had different effects on the lipid content of A549 cells. The FTIR spectra of the lipid exctracts of statin-treated A549 cells indicated that the value of hydrocarbon chain length, unsaturation index, oxidative stress level, and phospholipid containing lipids increased except for rosuvastatin-treated A549 cells. In addition, rosuvastatin significantly lowered cholesterol ester levels. In conclusion, the contrasting effects of rosuvastatin should be further investigated. 相似文献
7.
Recently, a new class of lipid lowering agents [3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors] was introduced
into clinical practice. The use of these agents could lead to a secondary deficiency in carnitine, which may manifest clinically
as a myalgia/myositis—a side effect that is occasionally seen with this class of drugs. In the present study, we examined
the effect of an HMG-CoA reductase inhibitor (lovastatin) on serum and tissue levels of carnitine and carnitine acyltransferase
activities in the rabbit. Rabbits (n=6) were fed chow containing lovastatin (30 mg/d) for 16 wk. Blood was collected and tissues (liver, heart, and skeletal muscle)
harvested at sacrifice. Free and total carnitine were measured in serum and tissues by a radioenzymatic method. Carnitine
acetyltransferase and carnitine palmitoyltransferase (CPT) activities were determined and expressed relative to DNA. Serum
free (24.0±2.6 vs. 29.4±3.1 μM) and total (35.1±4.7 vs. 52.8±8.8 μM) carnitine levels increased significantly with 16 wk of
treatment. This increase in total carnitine was mainly due to an increase in the levels of serum acylcarnitine (12.7±3.1 vs
26.5±5.7 μM). Tissue levels of total carnitine were significantly decreased by the treatment. Carnitine acetyltransferase
was unaffected by the treatment, whereas there was a significant increase in the activity of CPT in the liver and heart. 相似文献
8.
The effects of feeding diets containing either cholesterol (0.24% w/w) or cholestyramine (2.5% w/w) and of fasting on sterol
synthesis in the liver, ileum, and lung of both male and female guinea pigs have been studied by measuring the incorporation
by tissue slices of14C-labeled acetate into total digitonin-precipitable sterols. Cholesterol feeding significantly decreased (P<0.05) sterol synthesis
in the liver, ileum, and lung of the males and in the ileum of females. Cholestyramine feeding stimulated the rate of hepatic
sterol synthesis 13-fold but did not significantly affect sterologenesis in the ileum. Sterol synthesis in the lung was significantly
increased (P<0.05) but to a much lesser extent than in the liver. Fatty acid synthesis in the liver, ileum, and lung was not
significantly affected by either cholesterol or cholestyramine feeding. In guinea pigs fasted for 24 hr, sterol synthesis
was inhibited in all three tissues, the most pronounced effect occurring in the liver. Only in the lung was fatty acid synthesis
significantly decreased (P<0.001) by fasting. Cholesterol feeding resulted in increased concentrations of cholesterol in the
plasma and liver. Cholestyramine feeding reduced plasma cholesterol concentration by 81% in females and by 64% in males. However,
it did not significantly change the tissue cholesterol concentrations. Fasting resulted in a significant increase (P<0.05)
in plasma cholesterol concentration but did not affect the concentration of cholesterol in the tissues. It was concluded that
in the normal guinea pig, the feedback inhibition produced by both cholesterol and also possibly by bile acids suppresses
sterol synthesis in the liver to very low rates compared to those in the small intestine, where sterologenesis is not only
less sensitive to the cholesterol negative feedback system than that in the liver, but also is not subject to regulation by
the bile acid negative feedback system. 相似文献
9.
Roglans N Verd JC Peris C Alegret M Vázquez M Adzet T Díaz C Hernández G Laguna JC Sánchez RM 《Lipids》2002,37(5):445-454
Treatments with high doses of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors may induce the expression
of sterol regulatory element binding protein (SREBP)-target genes, causing different effects from those attributed to the
reduction of hepatic cholesterol content. The aim of this study was to investigate the effects of high doses of statins on
the key enzymes involved in VLDL production in normolipidemic rats. To examine whether the effects caused by statin treatment
are a consequence of HMG-CoA reductase inhibition, we tested the effect of atorvastation on these enzymes in mevalonatefed
rats. Atorvastatin and simvastatin enhanced not only HMG-CoA reductase but also the expression of the SREBP-2 gene itself.
As a result of the overexpression of SREBP-2 caused by the statin treatment, genes regulated basically by SREBP-1, as FA synthase
and acetyl-coenzyme A carboxylase, were also induced and their mRNA levels increased. DAG acyltransferase and microsomal IG
transfer protein mRNA levels as well as phosphatidate phosphohydrolase activity were increased by both statins. Simvastatin
raised liver cholesterol content, ACAT mRNA levles, and CTP:phosphocholine cytidylyltransferase activity, whereas it reduced
liver DAG and phospholipid content. Mevalonate feeding reversed all changes induced by the atorvastatin treatment. These results
show that treatment with high doses of statins induces key enzymes controlling rat liver lipid synthesis and VLDL assembly,
probably as a result of SREBP-2 overexpression. Despite the induction of the key enzymes involved in VLDL production, both
statins markedly reduced plasma TG levels, suggesting that different mechanisms may be involved in the hypotriglyceridemic
effect of statins at high or low doses. 相似文献
10.
The relative rates of sterol synthesis in the liver, ileum, and lung of the guinea pig have been studied by measuring the
incorporation by tissue slices of14C-labeled acetate into digitonin-precipitable sterols. The liver showed maximum incorporation of acetate at pH 6.5, the ileum
at pH 7.5, and the lung at pH 6.0. The incorporation of acetate approached the maximum rate at a concentration of 10 mM with
the liver and lung and 5 mM with the ileum. Using these conditions of assay, sterol synthesis was measured in the liver, ileum,
and lung of four groups of guinea pigs killed at 6-hourly intervals. Depending on the time of day, the rate of sterol synthesis
in the ileum was from 6 to 14 times that in the liver, while in the lung the rate was up to 3 times that shown by the liver.
Additional studies showed that all regions of the small intestine synthesized sterol at a higher rate than the liver, with
the highest rate of synthesis occurring in the ileum. The rates observed in the adrenal, testis, muscle, adipose tissue, and
skin indicated that these tissues are not quantitatively important sites of sterol synthesis in the guinea pig. 相似文献
11.
Perfluorodecanoic acid (PFDA) is a peroxisome proliferator that causes a dose-dependent (20–80 mg/kg) increase in hepatic
triacylglycerol and cholesteryl ester levels in the rat. We hypothesized that PFDA may cause an increase in thede novo synthesis of fatty acids and cholesterol in this species, which would explain observed effects. The incorporation of3H2O into tissue lipids was examined 7 days after rats received vehicle or 20 or 80 mg/kg of PFDA. PFDA treatment decreased the
rate of synthesis of cholesterol and fatty acids in the liver and in epididymal fat pad. At a PFDA dose (20 mg/kg) that decreasedde novo synthesis of fatty acids and cholesterol, there was no effect on the concentration of fatty acids and cholesterol in the
liver, epididymal fat pads, and plasma. We conclude that PFDA induced fatty liver is due to either a decrease in the oxidation
of fatty acids in the liver, or an impairment of triacylglycerol catabolism and/or export from the liver, and is not the result
of an increase inde novo synthesis of fatty acids and cholesterol. 相似文献
12.
Monoterpenes such as limonene and perillyl alcohol (PA) are currently under investigation for their chemotherapeutic properties
which have been tied to their ability to affect protein isoprenylation. Because PA affects the synthesis of isoprenoids’ such
as ubiquinone’ and cholesterol is the end product of the synthetic pathway from which this isoprenoid pathway branches’ we
investigated the effects of this compound upon cholesterol metabolism in the colonic adenocarcinoma cell line SW480. PA (1
mM) inhibited incorporation of 14C-mevalonate into 21–26 kDa proteins by 25% in SW480 cells. Cholesterol (CH) biosynthesis was assessed by measuring the incorporation
of 14C-acetate and 14C-mevalonate into 27-carbon-sterols. Cells treated with PA (1 mM) exhibited a fourfold increase in the incorporation of 14C-acetate but not 14C-mevalonate into cholesterol. Mevinolin (lovastatin)’ an inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase’
at 2 μM concentration’ inhibited CH synthesis from 14C-acetate by 80%. Surprisingly’ concurrent addition of mevinolin and PA did not significantly alter the stimulatory effects
of PA. As observed differences in 14C-acetate and 14C-mevalonate precursor labeling could indicate PA affects early pathway events’ the effects of this monoterpene on HMG-CoA
reductase activity were evaluated. Unexpectedly’ 1 mM PA did not stimulate activity of this enzyme. Consistent with its action
as a reversibly bound inhibitor’ in washed microsomes’ 2 μM mevinolin pretreatment increased reductase protein expression
causing a 12.7 (±2.4)-fold compensatory HMG-CoA reductase activity increase; concurrent treatment with 1 mM PA attenuated
this to a 5.3 (±0.03)-fold increase. Gas chromatographic analysis confirmed CH was the major lipid present in the measured
thin-layer chromatography spot. Since 14C-acetate incorporation into free fatty acid and phospholipid pools was not significantly affected by PA treatment’ nonspecific
changes in whole acetate pool sizes were not indicated. Because increases in endogenous CH synthesis should result in compensatory
changes in exogenous sterol utilization’ the effects of PA upon low density lipoprotein (LDL) receptor activity were evaluated.
Consistent with the observed increases in CH synthesis’ 1 mM PA decreased 125I-LDL internalization to 50% of the fetal bovine serum control; concurrent addition of 2 μM mevinolin attenuated this effect
to a reduction of 80% of the control value. Data suggest that in certain colonic tumor cells PA strongly affects cholesterol
metabolism via a mechanism of action that is insensitive to the HMG-CoA reductase inhibitor mevinolin. 相似文献
13.
The effects of 1, 5, 10 and 20 μg/kg dosages of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) upon de novo fatty acid and cholesterol synthesis in liver and adipose tissue were determined in pair-fed rats.
The incorporation of tritium from3H2O into tissue lipids was measured. Hepatic and adipose fatty acid synthetic rates (μmoles acetyl units g−1 hr−1 in the control groups were 19.6±4 and 75.7±18.5, respectively, and the liver cholesterol synthetic rate was 2.9±0.5 TCDD
(1 μg/kg) inhibited fatty acid synthesis in the liver and adipose tissue, by 44% and 41% respectively, and the liver cholesterol
synthesis was inhibited by 37%. The extent of these inhibitions increased with increasing dosages of TCDD. The effect of TCDD
on sterol synthesis in adipose tissue could not be determined, because the tritium incorporation into the sterol fraction
in this tissue was not detectable. 相似文献
14.
Bradford G. Stone Timothy J. Besse William C. Duane C. Dean Evans Eugene G. DeMaster 《Lipids》1993,28(8):705-708
Isoprene is a normal constituent of human breath and may be derived from the cholesterol synthetic pathway. Acute and chronic
lovastatin and a cholesterol-supplemented diet were used to determine whether a mechanistic link exists between isoprene and
cholesterol biosynthesisin vivo in humans. The acute effects of lovastatin, a competitive inhibitor of the rate-limiting step of cholesterol biosynthesis,
on breath isoprene excretion was determined by administering a single 20, 40 or 80 mg dose of this drug to five healthy male
subjects at 8 p.m. and measuring their breath isoprene levels every 4 h for one 24 h cycle before and after treatment. When
compared to the baseline cycle, all three doses of lovastatin significantly reduced breath isoprene levels at 6 and 10 h post-drug
treatment. Chronic lovastatin therapy (40 mg b.i.d. for 6 wk) reduced 6 a.m. breath isoprene levels (time of maximum baseline
value) by 27 ± 9% (SEM) and cholesterol synthesis measured in freshly isolated mononuclear leukocytes (ML) by 12 ± 6%. A cholesterol-supplemented
diet (1070 mg, total) ingested for 6 wk reduced breath isoprene excretion and ML sterol synthesis by 16 ± 5 and 19 ± 4%, respectively.
The parallel decreases in isoprene excretion and cholesterol synthesis caused by these pharmacologic and dietary means suggest
that breath isoprene is derived from the cholesterol synthesis pathway. 相似文献
15.
A number of free sterols and sterol esters of three freshwater mussels was separated and identified. A slow rate of biosynthesisde novo of sterols was demonstrated inAnodonta cygnea. Injected cholesterol was found to undergo esterification, oxidation, Δ22-dehydrogenation and C-24 alkylation. Methyl-[14C]methionine was proved to be incorporated in C-24 alkylsterols. Abnormally large amounts of cholesterol injected inA. cygnea were metabolized toward restoration of the normal composition of sterols. This was achieved by intensified metabolism of
cholesterol, mainly by conjugation, oxidation and Δ22-dehydrogenation. 相似文献
16.
Treatment of neonatal rats with U18666A, an inhibitor of desmosterol Δ24-reductase, results in accumulation of desmosterol (Δ5,24) and depletion of cholesterol (Δ5) in various bodily tissues and also causes cataracts. We evaluated the effects of U18666A on the sterol composition, de novo sterol synthesis, and histological structure of the retina. Neonatal Sprague-Dawley rats were injected subcutaneously with
U18666A (15 mg/kg, in olive oil) every other day from birth through 3 wk of age; in parallel, control rats received olive
oil alone. At 21 d, treated and control groups each were subdivided into two groups: one group of each was injected intravitreally
with [3H]acetate; retinas were removed 20 h later and non-saponifiable lipids (NSL) were analyzed by radio-high-performance liquid
chromatography. The other group was injected intravitreally with [3H]leucine; 4 d later, one eye of each animal was evaluated by light and electron microscopy and light microscopic autoradiography,
while contralateral retinas and rod outer segment (ROS) membranes prepared thereform were analyzed by sodium dodecyl sulfate-polyacrylamide
gel electrophoresis/fluorography. In the treated group, the Δ5/Δ5,24 mole ratio of retinas was ca. 1.0, and >88% of the NSL radioactivity was in Δ5,24; in contrast, control retinas had Δ5/Δ5,24 >170, with >80% of the NSL radioactivity in Δ5. Retinal histology, ultrastructure, ROS renewal rates, and rhodopsin synthesis and intracellular trafficking were comparable
in both treated and control animals. These results suggest that desmosterol can either substitute functionally for cholesterol
in the retina or it can complement subthreshold levels of cholesterol by sterol synergism. 相似文献
17.
Geranyl diphosphate (GPP), a 10-carbon isoprenoid, is a key intermediate in the isoprenoid biosynthetic pathway. This pathway,
in addition to leading to sterol synthesis, results in the synthesis of farnesyl diphosphate (FPP) and geranylgeranyl diphosphate
(GGPP), which serve as substrates for protein isoprenylation reactions. Basal levels of GPP in mammalian cells previously
have been undetectable. Here we present a novel, sensitive, nonradioactive method which allows for measurement of GPP in mammalian
cells. This methodology involves extraction of isoprenoids from cultured cells followed by enzymatic conjugation of GPP to
a fluorescent dansylated-peptide via farnesyl transferase and quantification with high-performance liquid chromatography (HPLC).
The lower limit of detection of GPP is 5 pg, or 0.015 pmol. Basal levels of GPP were determined in three human multiple myeloma
cell lines (RPMI-8226, U266, H929). Treatment of cells with inhibitors of the isoprenoid biosynthetic pathway results in marked
changes in GPP levels: the HMG-CoA reductase inhibitor lovastatin decreases GPP levels by over 50%, while the FPP synthase
inhibitor zoledronic acid increases GPP levels 16- to 107-fold. This method also allows for the simultaneous measurement of
GPP, FPP, and GGPP, thus leading to improved understanding of the pathway in a multitude of biological systems. Furthermore,
as drugs targeting this pathway are developed, their biological activity can be more directly linked to effects on isoprenoid
levels. 相似文献
18.
Tadashi Yoshida Akira Honda Junichi Shoda Masato Abei Yasushi Matsuzaki Naomi Tanaka Hiroshi Miyazaki Toshiaki Osuga 《Lipids》1997,32(8):873-878
Competitive inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase improve hypercholesterolemia. However, reports about the
effects of these agents on bile acid synthesis, the metabolic pathway of cholesterol, are conflicting. We studied the short-term
effect of one of these agents, pravastatin, on bile acid synthesis. Six male volunteers were given 40 mg of pravastatin. Plasma
mevalonate level (which reflects cholesterol synthesis) and 7α-hydroxy-4-cholesten-3-one level 9which reflects bile acid synthesis)
were measured every 2 h for 8 h. These plasma levels were compared to those of the same volunteers without pravastatin. Plasma
mevalonate level after 2 h was lower than control (3.0 ± 1.1 ng/ml vs. 6.7 ± 2.5, mean ±SD; P<0.05). This decrease continued for 8 h (2.5 ± 0.8 vs. 5.2 ± 1.5; P<0.05). On the other hand, plasma 7α-hydroxy-4-cholesten-3-one level did not change until after 6 h; then at 8 h it was lower
than control (15.7 ± 11.8 ng/mL vs. 24.7 ± 16.9; P <0.05). According to three-way layout analysis of variance, mevalonate level was influenced by both pravastatin treatment
(P<0.01) and time-course (P<0.01). On the other hand, the 7α-hydroxy-4-cholesten-3-one level was affected by both individual difference (P<0.01) and time course (P<0.01), but pravastatin treatment did not influence this compound. This indicates that bile acid synthesis was not influenced
by pravastatin, although cholesterol synthesis was inhibited. The shortterm inhibition of cholesterol synthesis did not affect
bile acid synthesis. 相似文献
19.
Policosanol, a well-defined mixture of very long chain primary alcohols that is available as a nutraceutical product, has
been reported to lower blood cholesterol levels. The present studies demonstrate that policosanol promotes the phosphorylation
of AMP-kinase and HMG-CoA reductase in hepatoma cells and in mouse liver after intragastric administration, providing a possible
means by which policosanol might lower blood cholesterol levels. Treatment of hepatoma cells with policosanol produced a 2.5-fold
or greater increase in the phosphorylation of AMP-kinase and HMG-CoA reductase, and increased the phosphorylation of Ca++/calmodulin-dependent kinase kinase (CaMKK), an upstream AMP-kinase kinase. Intragastric administration of policosanol to
mice similarly increased the phosphorylation of hepatic HMG-CoA reductase and AMP-kinase by greater than 2-fold. siRNA-mediated
suppression of fatty aldehyde dehydrogenase, fatty acyl-CoA synthetase 4, and acyl-CoA acetyltransferase expression in hepatoma
cells prevented the phosphorylation of AMP-kinase and HMG-CoA reductase by policosanol, indicating that metabolism of these
very long chain alcohols to activated fatty acids is necessary for the suppression of cholesterol synthesis, presumably by
increasing cellular AMP levels. Subsequent peroxisomal β-oxidation probably augments this effect. 相似文献
20.
The sterol substrate analog 25-thialanosterol and its corresponding sulfonium salt were evaluated for their ability to serve
as antifungal agents and to inhibit sterol methyltransferase (SMT) activity in Candida albicans. Both compounds inhibited cell proliferation, were fungistatic, interrupted the yeastlike-form to germ-tube-form transition,
and resulted in the accumulation of zymosterol and related Δ24-sterols concurrent with a decrease in ergosterol, as was expected for the specific inhibition of SMT activity. Feedback on
sterol synthesis was evidenced by elevated levels of cellular sterols in treated vs. control cultures. However, neither farnesol
nor squalene accumulated in significant amounts in treated cultures, suggesting that carbon flux is channeled from the isoprenoid
pathway to the sterol pathway with minor interruption or redirection until blockage at the C-methylation step. Activity assays using solubilized C. albicans SMT confirmed the inhibitors impair SMT action. Kinetic analysis indicated that 25-thialanosterol inhibited SMT with the
properties of a time-dependent mechanismbased inactivator K
i of 5 =gmM and apparent k
inact of 0.013 min−1, whereas the corresponding sulfonium salt was a reversible-type transition state analog exhibiting a K
i of 20 nM. The results are interpreted to imply changes in ergosterol homeostasis as influenced by SMT activity can control
growth and the morphological transition in C. albicans, possibly affecting disease development. 相似文献