| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Regulation of luteinizing hormone/chorionic gonadotropin receptor messenger ribonucleic acid expression in the rat ovary: relationship to cholesterol metabolism Wang, L. and K. M. Menon (2005), Endocrinology 146(1): 423-31. Abstract: Down-regulation of LH/human chorionic gonadotropin (hCG) receptor (LHR) mRNA in the ovary after the preovulatory LH surge or the administration of a pharmacological dose of LH/hCG occurs through a posttranscriptional mechanism. A LHR mRNA-binding protein was identified as the LHR mRNA destabilizing factor, and its identity was established as mevalonate kinase (Mvk). In the present study, we determined that, in the pseudopregnant rat ovary, LHR mRNA levels began to fall 4 h after hCG injection, at which time Mvk protein levels were elevated, and this elevation was preceded by an increase in Mvk mRNA levels. When the cytosolic fractions of hCG-treated ovaries were subjected to RNA EMSA, an increase in LHR mRNA-LHR mRNA-binding protein complex formation was observed, in parallel with the increase of Mvk expression. We also found that hCG coordinately up-regulated the expression of Mvk and other sterol-responsive elements containing cholesterol biosynthesis enzymes, such as 3-hydroxy-3-methylglutaryl-coenzyme A synthase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and farnesyl pyrophosphate synthase. This up-regulation was transient, but the hCG-induced ovarian cholesterol depletion lasted for more than 24 h. Taken together, our results suggest that, in the ovary, LH/hCG up-regulates the expression of cholesterol biosynthesis enzymes and lipoprotein receptors to replenish cellular cholesterol, and the up-regulation of Mvk leads to a down-regulation of LHR and suppresses the LH/hCG signal cascade transiently. Thus Mvk, an enzyme involved in cholesterol biosynthesis, serves as a link between LHR mRNA expression and cellular cholesterol metabolism. |
| Regulation of macrophage cholesterol efflux through hydroxymethylglutaryl-CoA reductase inhibition: a role for RhoA in ABCA1-mediated cholesterol efflux Argmann, C. A., J. Y. Edwards, et al. (2005), J Biol Chem 280(23): 22212-21. Abstract: The cholesterol biosynthetic pathway produces numerous signaling molecules. Oxysterols through liver X receptor (LXR) activation regulate cholesterol efflux, whereas the non-sterol mevalonate metabolite, geranylgeranyl pyrophosphate (GGPP), was recently demonstrated to inhibit ABCA1 expression directly, through antagonism of LXR and indirectly through enhanced RhoA geranylgeranylation. We used HMG-CoA reductase inhibitors (statins) to test the hypothesis that reduced synthesis of mevalonate metabolites would enhance cholesterol efflux and attenuate foam cell formation. Preincubation of THP-1 macrophages with atorvastatin, dose dependently (1-10 microm) stimulated cholesterol efflux to apolipoprotein AI (apoAI, 10-60%, p < 0.05) and high density lipoprotein (HDL(3)) (2-50%, p < 0.05), despite a significant decrease in cholesterol synthesis (2-90%). Atorvastatin also increased ABCA1 and ABCG1 mRNA abundance (30 and 35%, p < 0.05). Addition of mevalonate, GGPP or farnesyl pyrophosphate completely blocked the statin-induced increase in ABCA1 expression and apoAI-mediated cholesterol efflux. A role for RhoA was established, because two inhibitors of Rho protein activity, a geranylgeranyl transferase inhibitor and C3 exoenzyme, increased cholesterol efflux to apoAI (20-35%, p < 0.05), and macrophage expression of dominant-negative RhoA enhanced cholesterol efflux to apoAI (20%, p < 0.05). In addition, atorvastatin increased the RhoA levels in the cytosol fraction and decreased the membrane localization of RhoA. Atorvastatin treatment activated peroxisome proliferator activated receptor gamma and increased LXR-mediated gene expression suggesting that atorvastatin induces cholesterol efflux through a molecular cascade involving inhibition of RhoA signaling, leading to increased peroxisome proliferator activated receptor gamma activity, enhanced LXR activation, increased ABCA1 expression, and cholesterol efflux. Finally, statin treatment inhibited cholesteryl ester accumulation in macrophages challenged with atherogenic hypertriglyceridemic very low density lipoproteins indicating that statins can regulate foam cell formation. |
| Regulation of membrane cholesterol domains by sterol carrier protein-2 Hapala, I., J. Kavecansky, et al. (1994), Biochemistry 33(24): 7682-90. Abstract: Sterols are not randomly distributed in membranes but appear to be localized in multiple kinetic domains. Factors that regulate these sterol domains are not well-understood. A recently developed fluorescence polarization assay that measures molecular sterol transfer Butko, P., Hapala, I., Nemecz, G., of Schroeder, F. (1992) J. Biochem. Biophys. Methods 24, 15-37 was used to examine the mechanism whereby anionic phospholipids and liver sterol carrier protein-2 (SCP2) enhance sterol transfer. Two exchangeable and one very slowly or nonexchangeable sterol domain were resolved in phosphatidylcholine (POPC)/sterol small unilamellar vesicles (SUV). Inclusion of 10 mol % anionic phospholipids enhanced sterol exchange primarily by redistribution of sterol domain sizes rather than by alteration of half-times of exchange. This effect was dependent primarily on the percent content rather than the net charge per anionic phospholipid. In contrast, SCP2 simultaneously altered both the distribution of sterol molecules between kinetic domains and the exchange half-times of exchangeable sterol domains. The effects of SCP2 were much more pronounced when 10% acidic phospholipid was incorporated in the SUV. Compared to spontaneous sterol exchange, in the presence of 1.5 microM SCP2, the rapidly exchanging pool was increased by 36 to 330%, depending on the SUV phospholipid composition. Concomitantly, exchange half-times for rapidly and slowly exchangeable sterol were reduced by 60 to 98% for 1t1/2 and 14 to 85% for 2t1/2, respectively. The stimulatory effect of SCP2 was saturable and dependent both on protein concentration and on content of acidic phospholipids in membranes.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Regulation of mitochondrial cholesterol metabolism Martinez, F. and J. F. Strauss, 3rd (1997), Subcell Biochem 28: 205-34. |
| Regulation of murine plasma phospholipid transfer protein activity and mRNA levels by lipopolysaccharide and high cholesterol diet Jiang, X. C. and C. Bruce (1995), J Biol Chem 270(29): 17133-8. Abstract: Plasma phospholipid transfer protein mediates the net movement of phospholipids between lipoproteins and between lipid bilayers and high density lipoprotein. In this study, the mouse phospholipid transfer protein cDNA was cloned by reverse transcription polymerase chain reactions based on the cDNA sequence of human phospholipid transfer protein. The predicted amino acid sequence of mouse phospholipid transfer protein shows the protein to be 476 amino acids long and to have a sequence identity of 83% with that of human phospholipid transfer protein. Mouse plasma phospholipid transfer protein activity is 1.5-2 times that of human plasma phospholipid transfer protein activity. As in humans, mouse peripheral tissues displayed a higher abundance of phospholipid transfer protein mRNA than observed in central organs. The order of phospholipid transfer protein mRNA expression was as follows: lung > adipose tissue, placenta, testis > brain > muscle, heart, liver. We examined the regulation of phospholipid transfer protein expression by dietary cholesterol and by bacterial lipopolysaccharide. A high fat, high cholesterol diet caused a significant increase (35%) in plasma phospholipid transfer protein activity and a significant increase (18%) in high density lipoprotein phospholipids. This increased activity was accompanied by approximately 100% increase in phospholipid transfer protein mRNA in lung. After lipopolysaccharide injection, plasma phospholipid transfer protein activity was decreased by approximately 66%. This decrease in activity was associated with a similar decrease in phospholipid transfer protein mRNA in lung, adipose tissue, and liver. The decrease in plasma phospholipid transfer protein activity was also associated with a significant increase (17%) in high density lipoprotein phospholipid concentration. The opposite changes in phospholipids levels with lipopolysaccharide treatment and dietary cholesterol despite similarly increased high density lipoprotein phospholipids levels indicate that high density lipoprotein phospholipids levels are likely determined both by phospholipid transfer protein levels and by gradients of phospholipids concentration between high density lipoprotein and other phospholipids sources. |
| Regulation of neutral cholesterol esterase activity by cholesterol in J774 A.1 macrophages Tomita, T., S. Miura, et al. (1997), Ann N Y Acad Sci 811: 471-9. |
| Regulation of neutral cholesterol esterase activity by phospholipids containing negative charges in substrate liposome Ishii, I., R. Onozaki, et al. (1995), J Lipid Res 36(11): 2303-10. Abstract: The effect of phospholipids on cholesteryl ester hydrolysis by neutral cholesterol esterase in alveolar macrophages was studied. Among the phospholipids used as emulsifiers, those with a negative charge, such as phosphatidylserine, phosphatidic acid, phosphatidylinositol, and cardiolipin, gave a higher level of hydrolysis by neutral cholesterol esterase than other less negatively charged phospholipids, such as phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, and sphingomyelin. Phospholipase D treatment of liposomes emulsified with phosphatidylcholine produced phosphatidic acid and enhanced cholesteryl ester hydrolysis. Phospholipase A2 treatment produced lysophosphatidylcholine and decreased the hydrolysis. The hydrolysis of cholesteryl ester in lipid droplets obtained from cholesterol-laden macrophages elicited by thioglycollate in the rat peritoneal cavity was low compared to artificial liposomes emulsified with phosphatidylcholine. The reason for this was speculated to be that lipid droplets were low in total phospholipids and poor in phospholipids with strong negative charges but rich in phosphatidylethanolamine and sphingomyelin. These results suggest that the polar heads of phospholipids may play an important role in cholesteryl ester hydrolysis by neutral cholesterolesterase. |
| Regulation of pathways determining cholesterol availability in the baboon placenta with advancing gestation Shi, W., K. F. Swan, et al. (1999), Biol Reprod 61(6): 1499-505. Abstract: Low density lipoprotein (LDL) is accepted as the primary source of cholesterol for progesterone biosynthesis in the primate placental syncytiotrophoblast. We hypothesized that the syncytiotrophoblast may, however, derive significant amounts of cholesterol from sources in addition to the LDL pathway, especially during early pregnancy or when faced with a paucity of lipoprotein-cholesterol. To test this, alternate cholesterol-providing pathways were assessed in placentae at early (Days 60-61), mid (Days 98-102), and late (Days 160-167) gestation in the baboon (Papio sp., term approximately 184 days). Expression of LDL receptor mRNA transcripts in an enriched fraction of syncytiotrophoblast cells was approximately 13-fold greater (P < 0.05) in mid and late gestation than in early pregnancy, although no differences were observed in whole villous tissue. The abundance of transcripts for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme responsible for de novo cholesterol synthesis, remained unchanged in syncytiotrophoblast cells; however, HMG-CoA reductase activity declined approximately 2-fold from early to late pregnancy (P < 0.01), with a commensurate decline in immunoreactive HMG-CoA reductase protein. Activities for acyl-coenzyme A:cholesterol acyl transferase (ACAT), a rate-limiting enzyme for cholesterol esterification, were greater (P < 0.05) at early and mid pregnancy in placental homogenates than in those from late pregnancy, while ACAT-1 mRNA concentrations and cholesterol ester hydrolase activity remained unchanged. These results, taken together, suggest that although de novo synthesis has the potential to provide a measure of the cholesterol used for placental progesterone production during early baboon pregnancy, its contribution declines with advancing gestational age as LDL receptor-derived cholesterol becomes the major source of substrate. Changes in LDL receptor mRNA abundance suggest differences in mechanisms regulating cholesterol homeostasis in steroidogenically active syncytiotrophoblasts vs. proliferative nonendocrine cell types in the placenta. |
| Regulation of phospholipid biosynthesis during cholesterol influx and high density lipoprotein-mediated cholesterol efflux in macrophages Schmitz, G., M. Beuck, et al. (1990), J Lipid Res 31(10): 1741-52. Abstract: We have studied the rate of phospholipid synthesis and turnover in mouse peritoneal macrophages in reaction to cholesterol influx and high density lipoprotein (HDL)-mediated cholesterol efflux, using three different radioactive precursors, 32PO4(3-), 3Hcholine, and 14Coleic acid. The cells were loaded with cholesterol for up to 18 h with acetyl-low density lipoprotein (LDL), and phospholipid synthesis was measured at various time intervals and compared with nonloaded macrophages. In the first 2 h of cholesterol loading, a twofold increase in the rate of synthesis for sphingomyelin, phosphatidylcholine, phosphatidylserine-inositol, and phosphatidylethanolamine was observed. After this initial up-regulation, the rate of phospholipid synthesis continuously declined upon further cholesterol loading, while the turnover rate of cellular phospholipids was not affected under the same conditions. The lysosomal inhibitor chloroquine abolished the down-regulation, revealing a strong correlation between phospholipid synthesis and lysosomal enzyme activity which was presumably dependent on the release of cholesterol from the lysosome. The reduction in phospholipid synthesis induced by cholesterol loading is reversible by the addition of HDL3 to the cells. When HDL3 was added to the culture medium, a two- to threefold increase in phosphatidylcholine synthesis and a twofold increase in sphingomyelin formation was observed after 3 h. Ca2+ antagonists of the dihydropyridine type, which down-regulate HDL-receptor activity and promote the formation and cellular release of lamellar bodies derived from the lysosomal compartment (Schmitz, G., et al. 1988. Arteriosclerosis. 8: 46-56, and Robenek, H., and G. Schmitz. 1988. Arteriosclerosis. 8: 57-67), specifically enhance the synthesis of sphingomyelin in cholesterol-loaded macrophages. Inhibitors of acyl-CoA:cholesterol acyltransferase (Octimibate, progesterone) increase both the synthesis of sphingomyelin and phosphatidylcholine, and enhance HDL-receptor activity. The results indicate that cholesterol and phospholipid metabolism are coordinately regulated in macrophages. Moreover, the formation of phosphatidylcholine and sphingomyelin seems to be an important factor for the promotion of HDL-receptor-mediated cellular cholesterol efflux. |
| Regulation of plasma and liver total cholesterol levels by dietary oleic acid in rats fed a high-cholesterol diet Takeuchi, H., T. Kato, et al. (1999), J Nutr Sci Vitaminol (Tokyo) 45(1): 63-77. Abstract: The effects of diets containing fats and oils or fatty acids on the lipid metabolism were investigated in male rats of the Wistar strain fed hypercholesterolemic diets, especially focusing our attention on the correlation between dietary oleic acid (OLE) contents and the levels of plasma and liver total cholesterol (T-CHOL) or the fatty acid profiles in plasma and liver CHOL-ester. In the rats fed the free (FR)-type fatty acids, the concentrations of plasma and liver T-CHOL were high and the amounts of neutral steroids excreted into the feces were low when compared with those of rats given the triacylglycerol (TG)-type fatty acids, showing that TG-type fatty acids suppress the intestinal CHOL absorption more than the FR-type fatty acids do. The concentrations of plasma T-CHOL were highest in rats fed the oleic acid (OLE)-rich diets, followed in order by rats supplied with the palmitic acid (PAL)-rich diets, the hydrogenated coconut oil (HCO) diet, and the linoleic acid (LIN)-rich diets; the lowest was in rats given tristearin (TSTE) and linseed oil (LIS) diets. A positive correlation was obtained between the dietary OLE contents and the levels of plasma and liver T-CHOL or OLE in the plasma and liver CHOL-ester, and an inverse correlation between dietary OLE contents and the amounts of excreted neutral steroids. These results suggest that the dietary OLE contents regulate the levels of plasma and liver T-CHOL in CHOL-loaded rats. |
| Regulation of plasma HDL cholesterol and subfraction distribution by genetic and environmental factors. Associations between the TaqI B RFLP in the CETP gene and smoking and obesity Freeman, D. J., B. A. Griffin, et al. (1994), Arterioscler Thromb 14(3): 336-44. Abstract: This study investigated in a healthy population (n = 220) the association of the TaqI B restriction fragment length polymorphism (RFLP) in the cholesteryl ester transfer protein (CETP) gene with plasma high-density lipoprotein (HDL) cholesterol concentration and subfraction distribution. A raised HDL cholesterol level was found in B2B2 homozygotes (B2 cutting site absent) and was associated specifically with a 45% increase in HDL2 compared with B1B1 homozygotes (B1B1, 77 +/- 39 mg/100 mL, mean +/- SD; B2B2, 112 +/- 59 mg/100 mL; P < 0.01). Total plasma, very-low-density lipoprotein, and HDL triglyceride levels did not differ among the genotype groups, nor did plasma apolipoprotein AI levels (B1B1, 1.45 +/- 0.35 mg/mL, mean +/- SD; B2B2, 1.56 +/- 0.33 mg/mL). Thus, the genetic variation appeared to be independent of metabolic factors that are known to regulate HDL levels. Plasma CETP exchange activity was unlikely to be the cause of the association, since it did not differ between genotype groups and was not correlated with HDL2 concentration. Multivariate analysis demonstrated that the TaqI B polymorphism had an effect on HDL cholesterol and HDL2 that was independent of age, sex, body mass index, oral contraceptive use, exercise, alcohol consumption, and plasma triglycerides. In smokers, the presence of the B2B2 genotype did not result in increased HDL cholesterol or HDL2, whereas in obese subjects, the difference between B1B1 and B2B2 individuals was diminished. We conclude that the TaqI B RFLP is associated with a quantitatively significant effect on plasma HDL2 levels that is independent of plasma triglycerides and interacts with lifestyle factors. |
| Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids Spady, D. K., L. A. Woollett, et al. (1993), Annu Rev Nutr 13: 355-81. Abstract: Extensive data obtained in both experimental animals and humans demonstrate that steady-state plasma LDL-C concentrations are determined largely by the rate of LDL-C formation, Jt, and the level of LDL-R activity, Jm, located primarily in the liver. An increase in net cholesterol delivery to the liver suppresses Jm, slightly elevates Jt, and modestly raises the LDL-C level. Feeding lipids such as the 12:0, 14:0, and 16:0 saturated fatty acids further suppresses Jm, increases Jt, and markedly elevates the plasma LDL-C concentration. Feeding triacylglycerols containing the 18:1(c9) fatty acid restores hepatic receptor activity, decreases Jt, and modestly reduces the concentration of LDL-C in the plasma. The 18:2(c9, c12) compound has similar effects, although it is quantitatively less active than the monounsaturated fatty acid in restoring Jm. In contrast to these fatty acids that actively raise or lower hepatic receptor activity, a large group of compounds including the 4:0, 6:0, 8:0, 10:0, 18:0, and 18:1(t9) fatty acids have no demonstrable effect on any parameter of LDL-C metabolism. These fatty acids, therefore, can be added to animal and human diets with relative impunity. They will alter plasma LDL-C levels only to the extent that they replace the active saturated fatty acids (in which case they lower the LDL-C concentration) or unsaturated compounds (in which case they raise the plasma cholesterol level). All of these effects of cholesterol and the various fatty acids can be explained by the effects of these lipids in altering the size of the regulatory pool of cholesterol in the hepatocyte. However, many aspects of the cellular and molecular biology of these regulatory processes require additional investigation. In particular, new studies should focus on how the genetic background of an individual animal or human alters the quantitative response of its plasma LDL-C concentration to the dietary challenge of each of these types of lipids. |
| Regulation of receptor function by cholesterol Burger, K., G. Gimpl, et al. (2000), Cell Mol Life Sci 57(11): 1577-92. Abstract: Cholesterol influences many of the biophysical properties of membranes and is nonrandomly distributed between cellular organelles, subdomains of membranes, and leaflets of the membrane bilayer. In combination with the high dynamics of cholesterol distribution, this offers many possibilities for regulation of membrane-embedded receptors. Depending on the receptor, cholesterol can have a strong influence on the affinity state, on the binding capacity, and on signal transduction. Most important, cholesterol may stabilize receptors in defined conformations related to their biological functions. This may occur by direct molecular interaction between cholesterol and receptors. In this review, we discuss the functional dependence of the nicotinic acetylcholine receptor as well as different G protein-coupled receptors on the presence of cholesterol. |
| Regulation of reverse cholesterol transport and clinical implications Rader, D. J. (2003), Am J Cardiol 92(4A): 42J-49J. Abstract: Plasma levels of high-density lipoprotein (HDL) cholesterol and its major protein, apolipoprotein A-I, are inversely correlated with the incidence of atherosclerotic cardiovascular disease. Low HDL cholesterol and apolipoprotein A-I levels often are found in association with other cardiovascular risk factors, including the metabolic syndrome, insulin resistance, and type 2 diabetes mellitus. However, overexpression of apolipoprotein A-I in animals has been shown to reduce progression and even induce regression of atherosclerosis, indicating that apolipoprotein A-I is directly protective against atherosclerosis. A major mechanism by which apolipoprotein A-I inhibits atherosclerosis may be by promoting cholesterol efflux from macrophages and returning it to the liver for excretion, a process termed reverse cholesterol transport. This article focuses on new developments in the regulation of reverse cholesterol transport and the clinical implications of those developments. |
| Regulation of serum cholesterol level in middle-aged and elderly men. Relation of cholesterol absorption and synthesis to lipoprotein metabolism Gylling, H., T. Strandberg, et al. (1994), Arterioscler Thromb 14(5): 694-700. Abstract: The aim of the present study was to investigate cholesterol absorption and cholesterol and bile acid synthesis and relate these values of kinetics of low-density lipoprotein (LDL) apoprotein (apo) B in 50- and 75-year-old men to find out why and by which mechanism serum cholesterol level decreases with advancing age under normal home-living conditions. The daily calorie, fat, and cholesterol intakes were lower in the 75-year-old men because the physiological requirements of daily energy are reduced in old age. However, absolute body weight was identical in the two groups, indicating isocaloric energy intake. Serum levels of total and LDL cholesterol were insignificant lower but those of LDL apo B significantly lower, so that the LDL cholesterol/apo B ratio was higher in the elderly men. The mean reduction of LDL apo B by 26% (P <.05) in the old men was associated with a 30% (P <.05) decrease in transport rate (TR) and a 3% (P = NS) decrease in removal (FCR) for LDL apo B. However, at the comparable apo B levels, both TR and FCR for apo B were significantly lower in the old than in the younger men. Cholesterol absorption efficiency, bile acid synthesis, fecal neutral and total sterol excretion, and cholesterol turnover but not synthesis were reduced in the elderly men.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Regulation of serum HDL cholesterol and prevention of atherosclerosis Kahri, J. (2002), Duodecim 118(18): 1863-71. |
| Regulation of sodium channel function by bilayer elasticity: the importance of hydrophobic coupling. Effects of Micelle-forming amphiphiles and cholesterol Lundbaek, J. A., P. Birn, et al. (2004), J Gen Physiol 123(5): 599-621. Abstract: Membrane proteins are regulated by the lipid bilayer composition. Specific lipid-protein interactions rarely are involved, which suggests that the regulation is due to changes in some general bilayer property (or properties). The hydrophobic coupling between a membrane-spanning protein and the surrounding bilayer means that protein conformational changes may be associated with a reversible, local bilayer deformation. Lipid bilayers are elastic bodies, and the energetic cost of the bilayer deformation contributes to the total energetic cost of the protein conformational change. The energetics and kinetics of the protein conformational changes therefore will be regulated by the bilayer elasticity, which is determined by the lipid composition. This hydrophobic coupling mechanism has been studied extensively in gramicidin channels, where the channel-bilayer hydrophobic interactions link a "conformational" change (the monomer<-->dimer transition) to an elastic bilayer deformation. Gramicidin channels thus are regulated by the lipid bilayer elastic properties (thickness, monolayer equilibrium curvature, and compression and bending moduli). To investigate whether this hydrophobic coupling mechanism could be a general mechanism regulating membrane protein function, we examined whether voltage-dependent skeletal-muscle sodium channels, expressed in HEK293 cells, are regulated by bilayer elasticity, as monitored using gramicidin A (gA) channels. Nonphysiological amphiphiles (beta-octyl-glucoside, Genapol X-100, Triton X-100, and reduced Triton X-100) that make lipid bilayers less "stiff", as measured using gA channels, shift the voltage dependence of sodium channel inactivation toward more hyperpolarized potentials. At low amphiphile concentration, the magnitude of the shift is linearly correlated to the change in gA channel lifetime. Cholesterol-depletion, which also reduces bilayer stiffness, causes a similar shift in sodium channel inactivation. These results provide strong support for the notion that bilayer-protein hydrophobic coupling allows the bilayer elastic properties to regulate membrane protein function. |
| Regulation of stearoyl-CoA desaturase by polyunsaturated fatty acids and cholesterol Ntambi, J. M. (1999), J Lipid Res 40(9): 1549-58. Abstract: The lipid composition of cellular membranes is regulated to maintain membrane fluidity. A key enzyme involved in this process is the membrane-bound stearoyl-CoA desaturase (SCD) which is the rate-limiting enzyme in the cellular synthesis of monounsaturated fatty acids from saturated fatty acids. A proper ratio of saturated to monounsaturated fatty acids contributes to membrane fluidity. Alterations in this ratio have been implicated in various disease states including cardiovascular disease, obesity, non-insulin-dependent diabetes mellitus, hypertension, neurological diseases, immune disorders, and cancer. The regulation of stearoyl-CoA desaturase is therefore of considerable physiological importance and its activity is sensitive to dietary changes, hormonal imbalance, developmental processes, temperature changes, metals, alcohol, peroxisomal proliferators, and phenolic compounds. Two mouse and rat SCD genes (SCD1 and SCD2) and a single human SCD gene have been cloned and characterized. In the past several years we have studied the dietary influences on the genetic expression of the mouse stearoyl-CoA desaturase. The expression of the mouse SCD genes is regulated by polyunsaturated fatty acids and cholesterol at the levels of transcription and mRNA stability. Promoter elements that are responsible for the polyunsaturated fatty acid repression colocalize with the promoter elements for SREBP-mediated regulation of the SCD genes. It is the goal of this review to provide an overview of the genetic regulation of the stearoyl-CoA desaturase in response to dietary polyunsaturated fatty acids and cholesterol. |
| Regulation of sterol carrier protein 2 (SCP2) gene expression in rat peritoneal macrophages during foam cell formation. A key role for free cholesterol content Hirai, A., T. Kino, et al. (1994), J Clin Invest 94(6): 2215-23. Abstract: Sterol carrier protein 2 (SCP2) has been shown to be involved in intracellular transport and metabolism of cholesterol. However, there have been no reports concerning SCP2 in macrophages, the major source of atheromatous foam cells. We investigated whether SCP2 is present in rat peritoneal macrophages and determined the changes of SCP2 and its mRNA levels in macrophages during form cell formation induced by acetylated LDL (AcLDL). Immunoblot analysis and Northern blot analysis demonstrated that both SCP2 and its mRNA are expressed in rat peritoneal macrophages. Incubations with AcLDL caused a dose- and time-dependent increase of cellular esterified cholesterol, SCP2 and its mRNA in rat peritoneal macrophages. The inhibitor of acyl-CoA:cholesterol acyltransferase further enhanced AcLDL-induced increase of SCP2 protein and its mRNA. Incubations with 25-hydroxy cholesterol also caused a dose-dependent stimulation of SCP2 gene expression in macrophages, while incubation with maleylated BSA had no effect. These results suggest that the increment of cellular-free cholesterol is responsible for enhanced SCP2 gene expression in macrophages. The enhancement of SCP2 gene expression by AcLDL suggests that SCP2 may play an important role during foam cell formation induced by AcLDL which may be most important step for the atherosclerosis. |
| Regulation of sterol regulatory element-binding proteins by cholesterol flux in CaCo-2 cells Field, F. J., E. Born, et al. (2001), J Lipid Res 42(10): 1687-98. Abstract: The regulation of sterol regulatory element-binding proteins (SREBP) by cholesterol flux was studied in the intestinal cell line CaCo-2. CaCo-2 cells were incubated for 18 h with micelles containing 5 mM taurocholate and 500 microM oleic acid or micelles containing either 200 microM cholesterol or 150 microM lysophosphatidylcholine. In some incubations, an ACAT inhibitor was added or 25-hydroxycholesterol was substituted for cholesterol. The SREBP-1a transcript was 2-fold more abundant than the SREBP-1c transcript. In cells incubated with micelles containing cholesterol, rates of cholesterol synthesis were decreased and rates of esterification were increased. Cholesterol synthesis was decreased further by ACAT inhibition. Cholesterol influx decreased mRNA levels of SREBP-2, HMG-CoA synthase, HMG-CoA reductase, and fatty acid synthase. ACAT inhibition modestly suppressed gene expression further. Neither SREBP-1a nor SREBP-1c mRNA levels were altered by cholesterol. Despite decreases in gene expression of the sterol-responsive genes by cholesterol, the amounts of precursor and mature forms of SREBP-1 and SREBP-2 were not altered. In contrast, if 25-hydroxycholesterol was substituted for cholesterol, both the precursor and mature forms of SREBP-2 were decreased. The polar sterol decreased the mature form of SREBP-1 but the amount of the precursor form was unchanged. In cells incubated with micelles containing lysophosphatidylcholine, which causes cholesterol to efflux from cells, sterol-responsive gene expression was increased. The amounts of precursor and mature forms of SREBP-1 and SREBP-2, however, were not altered. In contrast, if the cells were depleted of cholesterol by incubating them with lovastatin and cyclodextrin, the mature forms of SREBP-1 and SREBP-2 were increased, as were mRNA levels for the sterol-responsive genes. The data would suggest that cholesterol influx/efflux regulates mRNA levels of sterol-responsive genes independently of changes in the amount of mature SREBP. In contrast, 25-hydroxycholesterol influx or cholesterol depletion alters the amount of mature SREBP, leading to the regulation of sterol-responsive gene expression. |