| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Regulation of cholesterol 7 alpha-hydroxylase gene expression in Hep-G2 cells. Effect of serum, bile salts, and coordinate and noncoordinate regulation with other sterol-responsive genes Taniguchi, T., J. Chen, et al. (1994), J Biol Chem 269(13): 10071-8. Abstract: Regulation of cholesterol 7 alpha-hydroxylase mRNA level in Hep-G2 cells was studied and compared with that of two other sterol-responsive genes, those for the low density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. In culture medium containing 10% fetal bovine serum (complete medium) for up to 24 h, the mRNA for cholesterol 7 alpha-hydroxylase gradually increased to 2-fold of the time 0 control. Culture of Hep-G2 cells in serum-free medium for 24 h resulted in stimulation of mRNA levels for LDL receptor (5-fold) and HMG-CoA reductase (6-fold). Surprisingly, the mRNA level for cholesterol 7 alpha-hydroxylase also increased 5-fold at 8 h and 4-fold at 24 h compared with the time 0 control. The addition of beta-migrating very low density lipoprotein (beta-VLDL) (40 micrograms/ml) and 25-hydroxycholesterol (5 micrograms/ml) prevented the increase in mRNA level for the LDL receptor, and HMG-CoA reductase and the levels were 10-26% of the control at 8 h. The effect with beta-VLDL was sustained for 24 h. With 25-hydroxycholesterol, both LDL receptor and HMG-CoA reductase mRNA returned to base line by 24 h. In contrast, beta-VLDL increased cholesterol 7 alpha-hydroxylase mRNA level above the serum-free control within 8 h (+32%), and this was sustained for 24 h (+47%). There was a slight induction of cholesterol 7 alpha-hydroxylase mRNA levels by 25-hydroxycholesterol at 8 h (+18%); but by 24 h, its level was below that of the control (-47%). There was no induction of cholesterol 7 alpha-hydroxylase mRNA levels by beta-VLDL or 25-hydroxycholesterol when the cells were grown in complete medium. As determined by nuclear run-on assay, the increase in the transcriptional rate of the cholesterol 7 alpha-hydroxylase gene in cells grown in serum-free medium (3.9-fold of the rate in complete medium) and incubated with beta-VLDL (+68% above serum-free control) at 8 h, was comparable with the increase in mRNA levels (3.5-fold and +32%, respectively). When bile salts were added to serum-free medium and cells cultured for up to 24 h, chenodeoxycholate and glycochenodeoxycholate caused a marked suppression of the level of cholesterol 7 alpha-hydroxylase mRNA, while cholate and its conjugates did not.(ABSTRACT TRUNCATED AT 400 WORDS) |
| Regulation of cholesterol 7 alpha-hydroxylase mRNA and transcriptional activity by taurocholate and cholesterol in the chronic biliary diverted rat Pandak, W. M., Y. C. Li, et al. (1991), J Biol Chem 266(6): 3416-21. Abstract: Cholesterol 7 alpha-hydroxylase catalyzes the rate-limiting step in the bile acid biosynthetic pathway. Regulation of this pathway is thought to occur solely as a result of a negative feedback control mechanism that is dependent upon the flux and composition of bile salts undergoing enterohepatic circulation. We have used the chronic biliary diverted (CBD) rat model to study the mechanism of regulation of cholesterol 7 alpha-hydroxylase by taurocholate. As compared to nonoperated controls, CBD rats exhibited a 4.2-fold increase in cholesterol 7 alpha-hydroxylase-specific activity, a 4.5-fold increase in enzyme mass, a 10-fold increase in steady-state mRNA levels, and a 3.4-fold increase in transcriptional (nuclear "run-on") activity. Intraduodenal infusion of taurocholate at a rate of 36 mumol/100 g/h for 48 h in CBD rats caused a significant (p less than 0.05) decrease (64%) in cholesterol 7 alpha-hydroxylase-specific activity, mass (72%), steady-state mRNA levels (74%), and transcriptional activity (57%) as compared to CBD controls. Cholesterol feeding increased cholesterol 7 alpha-hydroxylase-specific activity (288%), poly(A) RNA levels (291%), and transcriptional activity (220%) as compared to control animals. These results provide convincing evidence that bile salts, either directly or indirectly, down-regulate in vivo transcription of the cholesterol 7 alpha-hydroxylase gene, which is probably the major mechanism regulating the levels of this enzyme. The results of this study also suggest that the promoter for cholesterol 7 alpha-hydroxylase may have both bile salt- and sterol-responsive elements. |
| Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha) Chiang, J. Y., R. Kimmel, et al. (2001), Gene 262(1-2): 257-65. Abstract: The cholesterol 7alpha-hydroxylase gene (CYP7A1) plays an important role in regulation of bile acid biosynthesis and cholesterol homeostasis. Oxysterol receptor, LXR, stimulates, whereas the bile acid receptor, FXR, inhibits CYP7A1 transcription. The goal of this study was to investigate the role of LXRalpha on the regulation of rat, human and hamster CYP7A1 transcription in its native promoter and cellular context. Cotransfection with LXRalpha and RXRalpha expression plasmids strongly stimulated rat CYP7A1/luciferase reporter activity in HepG2 cells and oxysterol was not required. However, LXRalpha had much less effect on hamster and no significant effect on human CYP7A1 promoter activity in HepG2 cells. In Chinese hamster ovary cells, cotransfection with LXRalpha stimulated reporter activity by less than 2-fold and addition of 22(R)-hydroxycholesterol caused a small but significant stimulation of rat, human and hamster CYP7A1 promoter activity. At least two direct repeats of AGGTCA-like sequences with 4-base spacing (DR4) and five-base spacing (DR5), in previously identified bile acid response elements of the rat CYP7A1 were able to bind LXRalpha/RXRalpha and confer LXRalpha stimulation. However, LXRalpha did not bind to the corresponding sequences of the human gene and bound weakly to hamster and mouse DR4 sequences. Therefore, rats and mice have the unusual capacity to convert cholesterol to bile acids by LXRalpha-mediated stimulation of CYP7A1 transcription, whereas other species do not respond to cholesterol and develop hypercholesterolemia on a diet high in cholesterol. |
| Regulation of cholesterol 7alpha-hydroxylase mRNA expression in C57BL/6 mice fed an atherogenic diet Ando, H., S. Tsuruoka, et al. (2005), Atherosclerosis 178(2): 265-9. Abstract: The nuclear receptors liver X receptor (LXR) alpha and farnesoid X receptor (FXR) are positive and negative regulators of cholesterol 7alpha-hydroxylase (CYP7A1) transcription, respectively. To clarify their roles in the regulation of CYP7A1 in mice, we investigated mRNA expression of their target genes in the livers of C57BL/6 mice fed the following five diets for 2 weeks: a standard diet, cholic acid, cholesterol, cholesterol+high fat, or an atherogenic diet (cholic acid+cholesterol+high fat). The mRNA level of ATP-binding cassette transporter (ABC) A1 gene, one of LXRalpha target genes, significantly increased on the diets containing cholic acid and/or cholesterol+high fat, but not on the diet containing cholesterol alone. On the other hand, the mRNA levels of the FXR target genes ABCB11, ABCC2, and short heterodimer partner increased only on the diet containing cholic acid with or without cholesterol+high fat. Surprisingly, cholesterol alone or cholesterol+high fat did not affect CYP7A1 mRNA level, whereas cholic acid with or without cholesterol+high fat greatly reduced the level. Thus, in the atherogenic diet-fed mice, cholic acid component is needed for the FXR activation, and FXR dominantly regulates CYP7A1 transcription. |
| Regulation of cholesterol absorption in human and rat small intestine epithelial cells Safonova, I. G., D. D. Sviridov, et al. (1993), Biokhimiia 58(2): 274-84. Abstract: Cholesterol absorption in human small intestine organ culture and rat small intestine epithelial cell culture IRD-98 has been studied using 14C cholesterol, 3H cholesterol and 14C sitosterol. It has been found that cholesterol absorption is a dose- and time-dependent process, while sitosterol absorption is not and makes up to about 25% of the total cholesterol absorption. Cholesterol absorption appeared to be a specific process. The endocytosis inhibitor monensin decreased specific cholesterol absorption by 37%. Cholesterol absorption was examined under different conditions influencing cholesterol metabolism in the cell. Loading of IRD-98 cells with non-lipoprotein cholesterol caused a dose-dependent decrease of cholesterol absorption. The inhibitor of acyl coenzyme A:cholesterol acyl transferase (ACAT), compound Sandoz 58-035, had a similar effect on cholesterol absorption. Lovastatin, an inhibitor of 3-hydroxymethyl-3-glutaryl coenzyme A (HMG-CoA) reductase, stimulated cholesterol absorption in a dose-dependent manner. Loading of cells with cholesterol, lovastatin and Sandoz 58-035 had no effect on sitosterol absorption. The possibility has been demonstrated of using human small intestine organ culture and rat small intestine epithelial cell culture IRD-98 as models for studying cholesterol absorption. |
| Regulation of cholesterol and bile acid homoeostasis in bile-obstructed rats Dueland, S., J. Reichen, et al. (1991), Biochem J 280 (Pt 2): 373-7. Abstract: We examined how total blockage of biliary excretion, the major pathway through which cholesterol and bile acids are removed from the body, affects liver function, cholesterol and bile acid metabolism and homoeostasis. After 4 weeks of bile-duct ligation, rats showed impaired liver function, as documented by elevations in serum bilirubin and alkaline phosphatase activity. Moreover, bile-duct ligation decreased by about 30% both the amount of microsomal cytochrome P-450 in the liver and the elimination of aminopyrine in vivo, a reliable index in vivo of microsomal mixed-function oxidase activity. Cholesterol and bile acid contents in livers of bile-duct-ligated rats were doubled compared with sham-operated controls. Despite the increase in the contents of cholesterol and bile acids in liver, activities of the respective rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7 alpha-hydroxylase, were doubled. Serum concentrations of bile acids and free cholesterol increased 25- and 4-fold respectively. The large increase in serum bile acids was associated with a 380-fold increase in the urinary excretion of bile acids. Although there is a general decrease in cytochrome P-450 content and drug metabolism involving cytochrome P-450-containing hydroxylases, the activity of cholesterol 7 alpha-hydroxylase, also a cytochrome P-450-containing enzyme, is actually increased. These data show that complete obstruction of the bile duct results in the selective impairment of microsomal cytochrome P-450. Increased activity of 7 alpha-hydroxylase, bile acid synthesis and urinary excretion provides an alternative excretory pathway that helps to maintain cholesterol homoeostasis when the biliary excretory pathway is eliminated. |
| Regulation of cholesterol and lipoprotein metabolism in guinea pigs mediated by dietary fat quality and quantity Fernandez, M. L. and D. J. McNamara (1991), J Nutr 121(7): 934-43. Abstract: The effects of dietary fat quality and quantity on regulation of cholesterol and lipoprotein metabolism were measured in guinea pigs. The animals were fed 7.5 or 15% (wt/wt) fat diets containing either polyunsaturated corn oil (CO), monounsaturated olive oil (OL) or saturated lard as the fat source. Dietary fat quality had a number of significant effects: animals fed the CO-based diet had lower plasma LDL levels and LDL particles of higher density with decreased ratios of core-to-surface components. Apoprotein B/E receptor-mediated binding of LDL to hepatic membranes was twofold higher for animals fed the CO-based diet. Animals fed the OL-based diet had lower hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity and increased levels of hepatic cholesterol. Hepatic cholesteryl ester levels were lowest for animals fed the lard-based diet. Increasing dietary fat quantity resulted in increased plasma LDL levels and hepatic cholesterol, HMG-CoA reductase activity and receptor affinity for LDL. No changes were observed in LDL binding. These data demonstrate that, independent of dietary fat quantity, CO-based diets lower plasma LDL levels, modify LDL composition and increase hepatic apoprotein B/E receptor number. |
| Regulation of cholesterol biosynthesis by diet in humans Jones, P. J. (1997), Am J Clin Nutr 66(2): 438-46. Abstract: Biosynthesis of cholesterol represents a major input into whole-body pools; however, its regulation has been difficult to study in humans because of limitations in methodologies. The present objectives are to compare available techniques for measuring this process and examine how dietary factors alter human cholesterol biosynthesis. Review of existing techniques suggests that mass isotopomer distribution analysis and deuterium incorporation approaches offer advantages over other methods. Dietary factors influencing human cholesterol synthesis include energy restriction, meal frequency, dietary fat type, and cholesterol and phytosterol content. Food deprivation for as short as 24 h results in almost complete cessation of cholesterol biosynthesis. Similarly, increased meal frequency patterns are associated with a substantial depression in synthesis. In contrast, consumption of oils rich in polyunsaturated fatty acids, despite reducing circulating concentrations, increases the cholesterol synthesis rate compared with other fats. Stepwise addition of dietary cholesterol is associated with only a modest decline in cholesterogenesis while raising plasma concentrations slightly. It can be concluded that synthesis, as a contributor to circulating cholesterol concentrations, is sensitive to many dietary factors. Energy deprivation results in the greatest decline in synthesis, likely accounting for the beneficial decline in circulating cholesterol concentrations observed with weight loss. |
| Regulation of cholesterol biosynthesis in sitosterolemia: effects of lovastatin, cholestyramine, and dietary sterol restriction Nguyen, L. B., M. Cobb, et al. (1991), J Lipid Res 32(12): 1941-8. Abstract: We investigated the effects of lovastatin, cholestyramine, and dietary sterol restriction on cholesterol synthesis and low density lipoprotein receptor function in freshly isolated mononuclear leukocytes from two unrelated sitosterolemic families. Total plasma sterol concentrations were elevated in the two homozygous sitosterolemic subjects (343 and 301 vs. 185 mg/dl in controls) and contained increased amounts of plant sterols and 5 alpha-saturated stanols (20% and 8% vs. less than 1% in controls), but were not significantly different from controls in the two heterozygous subjects. The rates of conversion of acetate to cholesterol by mononuclear leukocytes were subnormal in all homozygous and heterozygous subjects and correlated with markedly reduced microsomal 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase activity. In the two homozygous subjects, cholestyramine treatment decreased plasma sterols 29% and 35%, and yet was associated with a paradoxical decline in mononuclear leukocyte HMG-CoA reductase activity. In contrast, plasma sterol concentrations decreased 14% and 5%, and mononuclear leukocyte HMG-CoA reductase activities increased 13% and 46% in three control and one heterozygous subjects treated with cholestyramine, respectively. Plasma sterol concentrations in the homozygous subjects unexpectedly failed to decline during treatment with lovastatin or a low sterol diet. In distinction, plasma sterol concentrations in three control and one heterozygous subjects dropped 28% and 31%, respectively, during treatment with lovastatin. Both cholestyramine and low dietary sterols stimulated low density lipoprotein receptor function. These results demonstrate a marked abnormality in cholesterol homeostasis in patients with homozygous sitosterolemia with xanthomatosis.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Regulation of cholesterol biosynthetic pathway in patients with the Smith-Lemli-Opitz syndrome Honda, M., G. S. Tint, et al. (2000), J Inherit Metab Dis 23(5): 464-74. Abstract: The Smith-Lemli-Opitz syndrome (SLOS) is a recessively inherited birth disorder caused by a defect in 7-dehydrocholesterol (3beta-hydroxysteroid) delta7-reductase, the final enzyme in cholesterol biosynthesis. To investigate in vivo regulation of the cholesterol biosynthetic pathway in SLOS, we measured hepatic microsomal sterol concentrations and activities of several key enzymes in the pathway, including HMG-CoA synthase, HMG-CoA reductase, squalene synthase and 7-dehydrocholesterol delta7-reductase in liver specimens from a patient with SLOS and 11 controls. Hepatic microsomal 7-dehydrocholesterol delta7-reductase activity in the patient was less than 1% of the control mean, and decreased cholesterol concentration and markedly increased 7- and 8-dehydrocholesterol concentrations were observed in the patient's microsomes. HMG-CoA synthase and squalene synthase activities in the patient were upregulated to 149% and 532%, respectively, while the activity of HMG-CoA reductase, the rate-limiting enzyme in the pathway, was reduced to 39% of the control mean. Downregulation of HMG-CoA reductase activity in SLOS was supported by measuring plasma levels of mevalonic acid, the immediate product of HMG-CoA reductase. The levels in SLOS patients (n = 9) were significantly low compared with age-matched controls (n = 8) (12+/-2 vs 28 + 6nmol/L, p < 0.05). These results suggest that in most SLOS patients in vivo HMG-CoA reductase is not stimulated in spite of blocked cholesterol biosynthetic pathway and reduced plasma and hepatic cholesterol concentrations. |
| Regulation of cholesterol distribution in macrophage-derived foam cells by interferon-gamma Panousis, C. G. and S. H. Zuckerman (2000), J Lipid Res 41(1): 75-83. Abstract: The Th1-derived cytokine gamma interferon, IFN-gamma, is present within the microenvironment of an atheromatous lesion and likely contributes to lesion progression through macrophage activation. While the inflammatory effects of IFN-gamma are well known, the role of this cytokine in cholesterol metabolism in macrophage derived foam cells is unclear. In the present study, the incubation of foam cells with IFN-gamma resulted in the reduction of HDL(3)-mediated cholesterol efflux. The decrease in cholesterol efflux was not observed with other macrophage-activating factors as colony-stimulating factors failed to demonstrate a similar effect. The reduction in cholesterol efflux was independent of apoE synthesis or SR-BI expression and was associated with a redistribution of intracellular cholesterol with an increase in cholesteryl ester accumulation. The increase in the esterified pool, primarily in cholesterol eicosapentadenoate, docosapentaenoate, arachidonate, and linoleate was associated with a 2-fold increase in acyl-CoA:cholesterol-O-acyltransferase, ACAT, activity and message without any change in neutral cholesteryl ester hydrolase activity. While CD36 message was reduced in IFN-gamma-treated foam cells, the ability to reverse the decrease in efflux by the ACAT inhibitor A58035 in a dose-dependent manner suggests that the IFN-gamma effect on efflux is primarily through the modulation of ACAT expression. Therefore, in addition to its inflammatory effects, IFN-gamma can contribute to the progression of an atherosclerotic lesion by altering the pathway of intracellular cholesterol trafficking in macrophage derived foam cells. |
| Regulation of cholesterol homeostasis and lipid metabolism in skeletal muscle by liver X receptors Muscat, G. E., B. L. Wagner, et al. (2002), J Biol Chem 277(43): 40722-8. Abstract: Recent studies have identified the liver X receptors (LXRalpha and LXRbeta) as important regulators of cholesterol and lipid metabolism. Although originally identified as liver-enriched transcription factors, LXRs are also expressed in skeletal muscle, a tissue that accounts for approximately 40% of human total body weight and is the major site of glucose utilization and fatty acid oxidation. Nevertheless, no studies have yet addressed the functional role of LXRs in muscle. In this work we utilize a combination of in vivo and in vitro analysis to demonstrate that LXRs can functionally regulate genes involved in cholesterol metabolism in skeletal muscle. Furthermore we show that treatment of muscle cells in vitro with synthetic agonists of LXR increases the efflux of intracellular cholesterol to extracellular acceptors such as high density lipoprotein, thus identifying this tissue as a potential important regulator of reverse cholesterol transport and high density lipoprotein levels. Additionally we demonstrate that LXRalpha and a subset of LXR target genes are induced during myogenesis, suggesting a role for LXR-dependent signaling in the differentiation process. |
| Regulation of cholesterol homeostasis by nuclear receptors Makishima, M. (2004), Seikagaku 76(6): 509-16. |
| Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system Whitney, K. D., M. A. Watson, et al. (2002), Mol Endocrinol 16(6): 1378-85. Abstract: The nuclear oxysterol receptors liver X receptor-alpha LXRalpha (NR1H3) and LXRbeta (NR1H2) coordinately regulate genes involved in cholesterol homeostasis. Although both LXR subtypes are expressed in the brain, their roles in this tissue remain largely unexplored. In this report, we show that LXR agonists have marked effects on gene expression in murine brain tissue both in vitro and in vivo. In primary astrocyte cultures, LXR agonists regulated several established LXR target genes, including ATP binding cassette transporter A1, and enhanced cholesterol efflux. In contrast, little or no effect on gene expression or cholesterol efflux was detected in primary neuronal cultures. Treatment of mice with a selective LXR agonist resulted in the induction of several LXR target genes related to cholesterol homeostasis in the cerebellum and hippocampus. These data provide the first evidence that the LXRs regulate cholesterol homeostasis in the central nervous system. Because dysregulation of cholesterol balance is implicated in central nervous system diseases such as Alzheimer's and Niemann-Pick disease, pharmacological manipulation of the LXRs may prove beneficial in the treatment of these disorders. |
| Regulation of cholesterol metabolism and low-density lipoprotein binding in human intestinal Caco-2 cells Reimann, F. M., G. Herold, et al. (1992), Digestion 51(1): 10-7. Abstract: In the present paper, the regulation of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, acylcoenzyme A cholesterol acyltransferase (ACAT) and low-density lipoprotein (LDL) binding was studied in the human colon cancer carcinoma cell line Caco-2. LDL down-regulated HMG-CoA reductase activity in a dose-dependent fashion to a minimum of 28% of control at 200 micrograms/ml and LDL binding to 52% of control. The activity of ACAT was stimulated by LDL. High-density lipoprotein 3 (HDL3) increased HMG-CoA reductase activity, whereas cholesteryl ester formation was slightly decreased. Inhibition of the endogenous cholesterol biosynthesis by mevinolin increased both LDL binding and activity of HMG-CoA reductase. This effect was reversed by the addition of mevalonolactone but not by LDL. It is concluded that regulation of HMG-CoA reductase and LDL binding is subject to the availability of non-sterol products of mevalonic acid and of exogenous cholesterol. ACAT is regulated mainly by the level of its substrate cholesterol. |
| Regulation of cholesterol metabolism by dietary plant sterols Miettinen, T. A. and H. Gylling (1999), Curr Opin Lipidol 10(1): 9-14. Abstract: Renewal has occurred in the use of plant sterols for the treatment of hypercholesterolemias. A novel development was to convert plant sterols to corresponding stanols and esterify them to fat soluble form. In contrast to the crystalline plant sterols or stanols, plant stanol esters can be easily consumed during normal food intake in soluble form in different fat-containing food constituents when they have a potent cholesterol-lowering effect, shown in normo- and hypercholesterolemic men and women without or with coronary heart disease, children and diabetes. Cholesterol lowering is approximately 10% for total and 15% for LDL cholesterol, with the respective values for stanol ester margarine (2-3 g/day stanols) being 15% and 20%. Stanol esters reduce cholesterol absorption efficiency by up to 65%, increase cholesterol elimination in feces as cholesterol itself, usually not as bile acids, and stimulate cholesterol synthesis. Serum beta-carotene level is lowered, but no fat malabsorption or lowering of serum fat soluble vitamins have been observed. In contrast to plant sterols, stanols and their esters are minimally absorbed and they reduce serum plant sterol concentrations, also preventing statin-induced increase of plant sterols. Stanol ester margarine has been included in dietary treatment of hypercholesterolemia followed by the addition of drug treatment in resistant cases. |
| Regulation of cholesterol metabolism by dietary protein and n-6 polyunsaturated fatty acids Huang, Y. S. (1990), J Nutr Sci Vitaminol (Tokyo) 36 Suppl 2: 169-72. Abstract: The modulating processes of dietary vegetable protein and polyunsaturated fatty acids (PUFAs) on cholesterol (CH) metabolism are very complicated. Since dietary protein can affect PUFA absorption and synthesis through the effects of its amino acid components, the CH-lowering of PUFAs may be modulated by dietary proteins. The effect of dietary PUFAs on the CH-lowering mechanism of vegetable proteins is mainly additive and complementary, but not competitive. Dietary vegetable protein reduces intestinal CH absorption, enhances catabolism of the CH-carrying lipoproteins, increases the LDL receptor activity, and modulates CH metabolic enzymes through the amino acid-modulated action of hormones. PUFAs may modulate CH metabolism through the action of eicosanoids which modulates the activity of the enzymes responsible for CH metabolism. |
| Regulation of cholesterol metabolism in adrenal cortex: comparative studies on cholesterol esterase in human adrenal glands Nishikawa, T., K. Mikami, et al. (1993), Endocr J 40(4): 453-9. Abstract: We have studied the nature and characteristics of cholesterol esterase (CEase) in human adrenal adenoma and hyperplasia tissues showing Cushing's syndrome, comparing with those in normal tissue. Each tissue demonstrated that two pH optima were found at around 4.5 and 8.0. The results of a subcellular distribution study show that acid and alkaline CEase are mainly located in lysosomes and microsomes, respectively. Our previous data suggested that phosphatidylcholine which was sonicated with cholesteryl oleate as a substrate may play a crucial role in the regulation of CEase in rat adrenal. The effect of phosphatidylcholine was therefore investigated in the present study. Acid CEase in normal tissue was increased in a dose-dependent manner by phosphatidylcholine, but not in the adenoma or hyperplasia tissues. None of those tissues showed any enhancement in alkaline CEase activity when phosphatidylcholine was added to the substrates. It is therefore suggested that the mechanism of regulation of CEase among three different kinds of human adrenals may be different from the data for the effect of phosphatidylcholine. Basal activity of acid CEase in adenoma and hyperplasia was significantly higher than that in normal tissue, and also that of alkaline CEase in hyperplasia tissue was significantly higher than that in normal tissue. Thus it is suggested that such an adrenocortical disorder as Cushing's syndrome due to adenoma and diffuse hyperplasia of the adrenal cortex may possess the nature and characteristics of autonomy of steroidogenesis which seems to be induced by the active metabolism of cholesterol, when compared with normal tissue. |
| Regulation of cholesterol metabolism in adrenal cortex: effects of apoproteins on cholesterol esterase in rat adrenal glands Nishikawa, T., K. Mikami, et al. (1993), Endocr J 40(2): 221-5. Abstract: We have investigated the effects of apoproteins on cholesterol esterase (CEase) in rat adrenal glands in order to clarify the mechanism of synthesis of free cholesterol which is the most important substrate for steroidogenesis. We prepared lipid mixtures containing cholesteryl oleate plus apoproteins with and without phosphatidylcholine as a substrate for CEase in order to investigate the effect of the substrate state on CEase. The substrate containing only cholesteryl oleate and apo-HDL increased both acid and alkaline CEase activities. Both acid and alkaline CEase activities were also increased by a substrate containing apo-HDL plus cholesteryl oleate and phosphatidylcholine more than by a substrate containing cholesteryl oleate plus apo-LDL with phosphatidylcholine or cholesteryl oleate with phosphatidylcholine. We have already reported that phosphatidylcholine is an important factor for the regulation of adrenal CEase. Therefore, the present studies show that apoproteins as well as phosphatidylcholine may be important factors for the regulation of adrenal CEase. |
| Regulation of cholesterol metabolism in the ethionine-induced premalignant rat liver Erickson, S. K., S. R. Lear, et al. (1990), J Lipid Res 31(5): 933-45. Abstract: The early premalignant liver provides a model in which to study metabolic alterations that may be permissive for the development of full malignancy. Although there are biochemical changes in this model, there are no detectable morphological ones when compared with a normal, fully differentiated liver. The maintenance of cholesterol homeostasis, essential for proper functioning of mammalian cells, is known to be altered in malignancy. We used the ethionine-induced premalignant liver model to study the effects of the premalignant state on cellular parameters involved in the maintenance of hepatic cholesterol homeostasis. Cholesterol synthesis was elevated about twofold in the livers of rats treated with ethionine as was the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, its rate limiting enzyme. There was no change in reductase activation state. Acyl coenzyme A:cholesterol acyl-transferase (ACAT) was decreased about 30%, and cholesterol 7 alpha-hydroxylase, about 50%. There was no significant change in neutral cholesteryl ester hydrolase activity, but acid hydrolase activity was decreased. There was little change in low density lipoprotein receptor protein as determined by immunoblotting. Biliary lipid secretion was in the normal range when expressed per gram liver; however, bile flow was doubled. The ethionine-fed animals were mildly hypocholesterolemic and had an altered serum lipoprotein pattern. Cholesterol synthesis and HMG-CoA reductase activity exhibited decreased sensitivities to inhibition by dietary cholesterol when compared to control livers. However, sensitivity to intragastrically administered mevalonolactone was not altered. Although ACAT activity was increased by mevalonolactone administration to levels similar to those in untreated animals, it was not increased in the ethionine-fed animals by feeding cholesterol. The ethionine-induced premalignant liver responded to ethinyl estradiol treatment in a manner similar to that of the control, i.e., profound hypolipidemia, increased low density lipoprotein receptors, decreased reductase activity, and increased cholesterol esterification. Thus, these livers retained their estrogen responsiveness. Taken together, the data demonstrate that the major elements involved in maintaining hepatic cholesterol homeostasis are present in the premalignant liver, although in some cases at levels that are different from the control. However, the susceptibility to regulation was altered in these livers to suggest markedly decreased availability of cholesterol of exogenous origin to the regulatory compartment(s). Further, coupling of the different elements involved in maintenance of hepatic cholesterol homeostasis appeared to have been changed. |