| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Regulation of cholesterol metabolism in the intestine Field, F. J., N. T. Kam, et al. (1990), Gastroenterology 99(2): 539-51. Abstract: The small intestine is a major site of cholesterol biosynthesis and lipoprotein degradation. It is also the organ responsible for absorbing dietary and endogenously produced biliary cholesterol. Cholesterol metabolism in the intestine is regulated by factors that will alter cellular cholesterol requirements. Thus, during increased cholesterol flux, which occurs by bile acid-faciliated cholesterol absorption or by lipoprotein-mediated uptake of cholesterol, cholesterol synthetic rates decrease and esterification rates increase. The mechanisms by which dietary fats regulate intestinal cholesterol metabolism are complex. Dietary fats alter membrane fatty acid composition. Simultaneously, they also promote lipoprotein secretion and alter cholesterol absorption. Intestinal 3-hydroxyl-3-methylglutaryl coenzyme. A reductase activity is regulated by enzyme phosphorylation-dephosphorylation. The regulation of acylcoenzyme A-cholesterol acyltransferase activity by this mechanism remains controversial. Data on hormone regulation of intestinal cholesterol metabolism are not conclusive, although progesterone seems to be a potent inhibitor of acylcoenzyme A-cholesterol acyltransferase activity in intestinal cell culture and isolated cells. In a manner similar to the regulation of cholesterol metabolism in other cells, the enterocyte responds appropriately to factors that alter cholesterol flux. Therefore, changes that occur in the rates of cholesterol synthesis and esterification will reflect the cholesterol requirements of the cell. |
| Regulation of cholesterol metabolism with dietary addition of oyster mushrooms (Pleurotus ostreatus) in rats with hypercholesterolemia Bobek, P., L. Ozdin, et al. (1997), Cas Lek Cesk 136(6): 186-90. Abstract: BACKGROUND: It is generally accepted that lowering of serum cholesterol levels reduces the risk of atherosclerosis. Identification and characterization of natural substances with hypocholesterolemic activity useful in dietetic prevention or treatment of hypercholesterolemia is still relevant in countries with persistent progression of hypercholesterolemia. Addition of oyster mushroom (Pleurotus ostreatus), an industrially produced wood-rotting fungus, to the diet effectively reduced cholesterol accumulation in serum and liver of rats fed a cholesterol diet. The aim of a series of experiments was to explain the biochemical mechanism of this effect. METHODS AND RESULTS: Male Wistar rats fed a cholesterol (0.3%) diet shortly after weaning for a period of 8-10 weeks were used in the experiments. The addition of 5% of dried oyster mushroom to the diet had following effects: reduction of cholesterol level both in serum (5.12 +/- 0.55 vs. 3.44 +/- 0.16 mmol/l, p < 0.02) and liver (241 +/- 12 vs. 113 +/- 11 mmol/kg, p < 0.001); redistribution of cholesterol in favour of high-density lipoproteins; reduced production of very-low-density lipoproteins (135 +/- 7 vs. 96.5 +/- 5 mumol/h/kg, p < 0.001); reduced cholesterol absorption (61.2 +/- 2 vs. 53 +/- 2%, p < 0.02) and reduced HMG-CoA activity in liver (137 +/- 16 vs. 86 +/- 9 pmol/min/mg proteins, p < 0.02). Simultaneously, an increase in 7 alfa-hydroxylase activity in liver (17 +/- 1 vs. 22 +/- 1 pmol/min/mg proteins. p < 0.02) and bile acid excretion (7 +/- 0.9 vs. 11 +/- 0.5 mg/day/rat, p < 0.02) was observed. (Values shown are means +/- SEM.) CONCLUSIONS: Biochemical mechanism of hypocholesterolemic effect of oyster mushroom on cholesterol-fed rats includes reduced production of cholesterol-rich very-low-density and low-density lipoproteins which principally determine cholesterol levels in serum. This effect is related to decreased absorption and biosynthesis of cholesterol together with increase in cholesterol catabolism and excretion of degradation products-bile acids. |
| Regulation of cholesterol responsive genes in ovary cells: impact of cholesterol delivery systems Medicherla, S., S. Azhar, et al. (1996), Biochemistry 35(20): 6243-50. Abstract: The "selective" cholesterol uptake pathway represents a bulk pathway by which many steroidogenic cells internalize lipoprotein-delivered cholesteryl esters. In the current report, we question whether cholesteryl esters entering cells via this pathway are capable of governing standard cholesterol end product feedback repression mechanisms. Cultured rat ovary granulosa cells which utilize both the "selective" and "endocytic" pathways to internalize lipoprotein-derived cholesteryl esters were used as a model system. ApoE-free hHDL3 was used to deliver cholesteryl esters to the cells exclusively by the selective pathway; hLDL was used as a control ligand which when internalized by the endocytic pathway releases cholesteryl esters which subsequently regulate the expression of the B/E (LDL)-receptor, HMG CoA reductase, and acyl-CoA:cholesterol acyltransferase (ACAT). Whereas trophic hormone (Bt2cAMP) stimulation by itself increased the activity, mRNA, and protein levels of both B/E-receptor and HMG CoA reductase, pretreatment with either lipoprotein (adjusted for equal cholesterol ester content) down-regulated this expression. Linked with these lipoprotein-related changes was an increase in activity (though not gene expression) of ACAT. The level of change in mRNA levels, protein content, and activity for the examined regulatory proteins was essentially equivalent whether the lipoprotein provided to the cells was hLDL or hHDL3. Thus, similar signals appear to have been received by the cells despite differences in the uptake and processing of the ligand-derived cholesteryl esters, and these signals resulted in identical homeostatic responses by the cells. |
| Regulation of cholesterol supply for mineralocorticoid biosynthesis Capponi, A. M. (2002), Trends Endocrinol Metab 13(3): 118-21. Abstract: In addition to intracellular cholesterol synthesis, plasma low- and high-density lipoproteins (LDL and HDL, respectively) are the major potential sources of a cholesterol precursor for steroid synthesis in all steroidogenic tissues. LDL- and HDL-cholesterol are taken up by cells through entirely distinct mechanisms. In the case of aldosterone production in the zona glomerulosa of the adrenal cortex, it has been assumed in the past that LDL is the major supplier of cholesterol. However, recent developments, in particular the discovery of the scavenger receptor class B type I for HDL and the characterization of its properties, have questioned this view. In fact, the nature of the challenging factor (angiotensin II or adrenocorticotropic hormone) appears to determine which pool of cholesterol is preferentially mobilized and which pathway (LDL receptor endocytosis or selective uptake through the HDL receptor) is regulated. |
| Regulation of cholesterol synthesis and esterification in primary cultures of macrophages following uptake of chylomicron remnants Yu, K. C. and J. C. Mamo (1997), Biochem Mol Biol Int 41(1): 33-9. Abstract: The effects of chylomicron remnants (CR), beta-very-low-density-lipoproteins (beta-VLDL) and low-density-lipoproteins (LDL) on intracellular cholesterol synthesis and esterification in primary rabbit macrophages was determined by assaying for HMG-CoA reductase activity and cholesterol esterification. At physiological cholesterol concentrations, both CR and LDL inhibited cholesterol synthesis by almost 60% while beta-VLDL was less potent achieving only 30% inhibition. Cholesterol esterification rates were increased four-fold by CR and LDL, whereas beta-VLDL increased esterification 14 times above controls. Qualitatively, the effect of CR on cholesterol synthesis and esterification in rabbit macrophages differs from observations in transformed macrophage cells. Quantitatively, the enhanced rates of cholesterol esterification and weak inhibition of cholesterol synthesis following beta-VLDL uptake may explain why this lipoprotein rapidly induces foam cell formation in vitro. |
| Regulation of cholesterol synthesis by oleic and palmitic acid in keratinocytes Siefken, W., H. Hoppner, et al. (2000), Exp Dermatol 9(2): 138-45. Abstract: Cholesterol synthesis is essential for homeostasis of the epidermis, being required for both cell division and differentiation, as well as maintenance of the epidermal permeability barrier. Cholesterol synthesis in keratinocytes has been demonstrated to be regulated by sterol levels and the barrier function of the stratum corneum. Cholesterol synthesis in the epidermis is correlated with changes in mRNA levels for key enzymes, such as HMG-CoA synthase and HMG-CoA reductase, which have been previously demonstrated to be coordinately regulated by the sterol regulatory element binding proteins (SREBPs). In this study we demonstrate that a functional sterol regulatory element is required for sterol regulation of HMG-CoA synthase in keratinocytes. We also investigate the regulation of cholesterol synthesis by fatty acids, which are another important constituent of the stratum corneum lipids. Palmitic and oleic acid inhibit 14C-labelled acetate incorporation into sterols in a similar manner to sterols. However, unlike sterols, 50 microM oleic acid increase the steady state mRNA levels of HMG-CoA synthase and the activity of the HMG-CoA synthase promoter. The addition of 50 microM oleic acid to 25-hydroxycholesterol results in an enhancement of the inhibitory effect of the sterol on promoter activity. The inhibition of acetate incorporation into sterols in human keratinocytes by 50 microM palmitic and 50 microM oleic acid is not due to regulation of HMG-CoA synthase at the level of transcription. |
| Regulation of cholesterol synthesis in four colonic adenocarcinoma cell lines Cerda, S. R., J. t. Wilkinson, et al. (1995), Lipids 30(12): 1083-92. Abstract: Colon tumor cells, unlike normal human fibroblasts, exhibited an uncoupling of low density lipoprotein (LDL)-derived cholesterol from cellular growth, when endogenous cholesterol synthesis was inhibited by mevinolin, a hydroxymethylglutaryl-CoA reductase (HMG-CoAR) competitive inhibitor Fabricant, M., and Broitman, S.A. (1990) Cancer Res. 50, 632-636. Further evaluation of cholesterol metabolism was conducted in two undifferentiated (SW480, SW1417) and two differentiated (HT29, CACO2) colonic adenocarcinoma (adeno-CA) cell lines and an untransformed human fibroblast, AG1519A. Cells grown in monolayer culture to near subconfluency were used to assess endogenous cholesterol synthesis by 14C-acetate incorporation, in response to the following treatments in lipoprotein-deficient serum (LPDS)-supplemented minimum essential medium (MEM): LPDS alone, LDL, mevinolin, mevinolin with LDL, and 25-hydroxy-cholesterol (25-OH-CH). Complete fetal bovine serum (FBS)-supplemented MEM was used as control. All colon tumor lines exhibited similarly high endogenous cholesterol synthesis in both FBS and LPDS relative to the fibroblasts which demonstrated low basal levels in FBS and maximal synthesis in LPDS. LDL treatment did not inhibit cholesterol synthesis in colon tumor cells, but suppressed that in the fibroblast by 70%. Sterol repression of cholesterol synthesis mediated by 25-OH-CH occurred in all cells. Mevinolin caused a reduction in cholesterol synthesis in the colonic cancer cell lines, which was not further decreased by concurrent addition of LDL. In contrast, in mevinolin-treated fibroblasts, LDL further inhibited cholesterol synthesis. When the effect of cell density on cholesterol synthesis regulation was evaluated under conditions of sparse density in SW480 and SW147, results indicated that (i) basal rates of cholesterol synthesis were higher, (ii) LDL inhibited cholesterol synthesis more effectively, and (iii) mevinolin or 25-OH-CH had a more pronounced effect than in subconfluent cells. Evaluation of LDL receptor activity through 125I-LDL binding and internalization studies demonstrated LDL receptor expression was reduced by 37% in normal density cells relative to the low density cultures. In contrast to cholesterol synthesis, exogenous LDL could inhibit LDL receptor activity at both densities. Thus subconfluent growing colonic adenoCA cell lines retain the capacity for sterol repression, but, in contrast to normal fibroblasts, exhibit a high endogenous cholesterol synthesis which LDL cannot regulate. |
| Regulation of cholesterol synthesis: of SCAP, SREBP, CBP and more Meier, C. A. (1997), Eur J Endocrinol 136(3): 271-2. |
| Regulation of cholesterol uptake in the rat intestinal cell line Safonova, I. G., D. D. Sviridov, et al. (1994), Biochim Biophys Acta 1210(2): 181-6. Abstract: A new model to study cholesterol absorption in the rat intestinal cells is described. Rat intestine epithelial cells IRD98 were incubated with mixed micelles containing bile acid, phospholipid, cholesterol or its nonabsorbable analogue, sitosterol, and trace amounts of 3Hcholesterol or 14Csitosterol. Cholesterol and sitosterol uptake was then determined following lipid extraction; specific cholesterol uptake was determined as the difference between cholesterol and sitosterol uptake. Cholesterol, but not sitosterol, uptake was time- and dose-dependent and saturable. Loading of cells with non-lipoprotein cholesterol reduced cholesterol, but not sitosterol, uptake in a dose-dependent manner. In contrast, treatment of cells with an inhibitor of cholesterol synthesis, lovastatin, stimulated cholesterol, but not sitosterol, uptake in a dose-dependent manner. Treatment of cells with palmitic, caproic and oleic acids up-regulated specific cholesterol uptake, while linoleic and stearic acids had an opposite effect. None of the fatty acids affected sitosterol uptake. |
| Regulation of cholesterol/lipid biosynthetic genes by Egr2/Krox20 during peripheral nerve myelination Leblanc, S. E., R. Srinivasan, et al. (2005), J Neurochem 93(3): 737-48. Abstract: Myelination of peripheral nerves by Schwann cells requires a large amount of lipid and cholesterol biosynthesis. To understand the transcriptional coordination of the myelination process, we have investigated the developmental relationship between early growth response 2 (Egr2)/Krox20--a pivotal regulator of peripheral nerve myelination--and the sterol regulatory element binding protein (SREBP) pathway, which controls expression of cholesterol/lipid biosynthetic genes. During myelination of sciatic nerve, there is a very significant induction of SREBP1 and SREBP2, as well as their target genes, suggesting that the SREBP transactivators are important regulators in the myelination process. Egr2/Krox20 does not appear to directly regulate the levels of SREBP pathway components, but rather, we found that Egr2/Krox20 and SREBP transactivators can synergistically activate promoters of several SREBP target genes, indicating that direct induction of cholesterol/lipid biosynthetic genes by Egr2/Krox20 is a part of the myelination program regulated by this transactivator. |
| Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP Davis, R. A., J. H. Miyake, et al. (2002), J Lipid Res 43(4): 533-43. Abstract: Cholesterol-7alpha-hydroxylase (CYP7A1) regulates the pathway through which cholesterol is converted into bile acids. The unique detergent properties of bile acids are essential for the digestion and intestinal absorption of hydrophobic nutrients. Bile acids have potent toxic properties (e.g., membrane disruption) and there are a plethora of mechanisms to limit their accumulation in blood and tissues. The discovery of farnesoid X receptor (FXR), the nuclear receptor activated specifically by bile acids, has opened new insights into these mechanisms. Bile acid activation of FXR has been shown to repress the expression of CYP7A1 via increasing the expression of small heterodimer partner (SHP), a non-DNA binding protein. The increased abundance of SHP causes it to associate with liver receptor homolog (LRH)-1, an obligate factor required for transcription of CYP7A1. Recent studies show there is an "FXR/SHP-independent" mechanism that also represses CYP7A1 expression. This "FXR/SHP-independent" pathway involves the interaction of bile acids with liver macrophages (i.e., Kupffer cells), which induces the expression, and secretion of cytokines.These inflammatory cytokines, which include tumor necrosis factor alpha and interleukin-1beta, act upon liver parenchymal cells causing a rapid repression of the CYP7A1 gene. |
| Regulation of classic and alternative bile acid synthesis in hypercholesterolemic rabbits: effects of cholesterol feeding and bile acid depletion Xu, G., G. Salen, et al. (1998), J Lipid Res 39(8): 1608-15. Abstract: The effect of cholesterol feeding (3 g/day) on bile acid synthesis was examined in 10 New Zealand white rabbits (NZW), 8 Watanabe heterozygous and 10 homozygous rabbits with partial and complete deficiencies of LDL receptors. After 10 days of cholesterol feeding, bile fistulas were constructed and bile acid pool sizes were measured. Cholesterol feeding increased plasma and hepatic cholesterol levels in all rabbit groups. Baseline bile acid pool sizes were smaller (P < 0.01) in heterozygotes (139 +/- 3 mg) and homozygotes (124 +/- 30 mg) than NZW rabbits (254 +/- 44 mg). After feeding cholesterol, bile acid pool sizes doubled with increased cholic acid synthesis in NZW and, to a lesser extent, in Watanabe heterozygous rabbits but not in homozygotes. Baseline cholesterol 7alpha-hydroxylase activity in NZW and heterozygotes declined 69% and 53% (P < 0.001), respectively, after cholesterol feeding. Sterol 27-hydroxylase activity reflecting alternative bile acid synthesis increased 66% (P < 0.01) in NZW and 37% in Watanabe heterozygotes but not in homozygotes after feeding cholesterol. Bile fistula drainage stimulated cholesterol 7alpha-hydroxylase activity but not sterol 27-hydroxylase activity in all three rabbit groups. These results demonstrated that dietary cholesterol increased hepatic sterol 27-hydroxylase activity and alternative bile acid synthesis to expand the bile acid pool and inhibited cholesterol 7alpha-hydroxylase in NZW and in Watanabe heterozygous rabbits but not in homozygotes with absent hepatic LDL receptor function. Thus, in rabbits, sterol 27-hydroxylase is up-regulated by the increased hepatic cholesterol that enters the liver via LDL receptors whereas cholesterol 7alpha-hydroxylase is controlled by the circulating hepatic bile acid flux. |
| Regulation of cytochrome P450 cholesterol side-chain cleavage, 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase type 1 and estradiol-17 beta-hydroxysteroid dehydrogenase mRNA levels by calcium in human choriocarcinoma JEG-3 cells Beaudoin, C., M. Bonenfant, et al. (1997), Mol Cell Endocrinol 133(1): 63-71. Abstract: In human placenta the cytochrome P450 side-chain cleavage (P450scc) and 3 beta-hydroxysteroid dehydrogenase type 1 (3 beta-HSD-1) convert cholesterol and pregnenolone producing progesterone, whereas 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD-1) mediates the interconversion of estrone and estradiol. We have examined the effects of calcium on phorbol ester- and cAMP-induced P450scc, 3 beta-HSD-1 and 17 beta-HSD-1 mRNAs in human JEG-3 cells. A23187 increased in a dose-dependent fashion in the 1.3 kb 17 beta-HSD-1 mRNA whereas a weaker increase followed by a gradual depletion effect of A23187 was observed on 3 beta-HSD-1 mRNA. No significant effect of A23187 on P450scc mRNA was observed. Using 0.50 microM of A23187 the induction of 3 beta-HSD-1 and 17 beta-HSD-1 mRNAs was maximum within about 6 h whereas P450scc mRNA levels stayed unaffected throughout the time-course period. The action of A23187 was synergistic on cAMP-stimulated 17 beta-HSD-1 mRNA levels, while in a dose-dependent manner A23187 progressively depleted 3 beta-HSD-1 and P450scc mRNA abundance probably by activation of a calcium-/calmodulin-dependent phosphodiesterase. On the phorbol 12-myristate, 13-acetate (PMA)-stimulated 3 beta-HSD-1, 17beta-HSD-1 and P450scc mRNA levels only the lowest concentration of A23187 potentialized the PMA effect on the 17 beta-HSD-1 mRNA levels. Using thapsigargin (TG), a cell-permeable sesquiterpene lactone that releases calcium by inhibiting sarco/endoplasmic reticular calcium-ATPase, our data indicated the presence in JEG-3 cells of TG-sensitive and TG-insensitive calcium-ATPases regulating 3 beta-HSD-1 and 17 beta-HSD-1 mRNA levels. These results emphasized the complexity of calcium contribution with the protein kinase A and C pathways in the regulation of P450scc, 3 beta-HSD-1 and 17 beta-HSD-1 mRNA levels. In addition, the different sensitivity of these genes to calcium suggest they could be activated by different subclasses of PKCs. |
| Regulation of early cholesterol biosynthesis in rat liver: effects of sterols, bile acids, lovastatin, and BM 15.766 on 3-hydroxy-3-methylglutaryl coenzyme A synthase and acetoacetyl coenzyme A thiolase activities Honda, A., G. Salen, et al. (1998), Hepatology 27(1): 154-9. Abstract: Cytosolic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase catalyzes the formation of HMG-CoA, the substrate for the rate-controlling enzyme in the cholesterol biosynthetic pathway. To explore the regulation in liver, we developed a new, accurate, and reliable reversed-phase ion-pair chromatographic assay that uses nonradioactive substrates and n-propionyl coenzyme A as an internal recovery standard. The hepatic activities were measured in rats treated with cholesterol, sitosterol, cholic acid, deoxycholic acid, ursodeoxycholic acid, cholestyramine, bile fistula, lovastatin, and BM 15.766, an inhibitor of 7-dehydrocholesterol delta7-reductase, and were compared with microsomal HMG-CoA reductase and cytosolic acetoacetyl coenzyme A (AcAc-CoA) thiolase activities. HMG-CoA synthase activity was effectively suppressed in synchrony with HMG-CoA reductase activity by treatments with cholesterol (-41%, P <.05), cholic acid (-72%, P <.005), and deoxycholic acid (-62%, P <.05). However, ursodeoxycholic acid increased activity 84% (P <.05) and intravenous sitosterol did not change activity. AcAc-CoA thiolase activities also paralleled HMG-CoA reductase and HMG-CoA synthase activities, but differences were not statistically significant. In contrast to inhibition, up-regulation of hepatic HMG-CoA synthase activities by cholestyramine, bile fistula, and lovastatin was much less than HMG-CoA reductase activities. In addition, BM 15.766 did not stimulate synthase activity, whereas lovastatin increased activity 2.4-fold. Thus, hepatic HMG-CoA synthase activity was regulated coordinately with HMG-CoA reductase, and responded more forcefully to regulatory stimuli than acetoacetyl-CoA thiolase activity but usually less than HMG-CoA reductase. |
| Regulation of endoplasmic reticulum cholesterol by plasma membrane cholesterol Lange, Y., J. Ye, et al. (1999), J Lipid Res 40(12): 2264-70. Abstract: The abundance of cell cholesterol is governed by multiple regulatory proteins in the endoplasmic reticulum (ER) which, in turn, are under the control of the cholesterol in that organelle. But how does ER cholesterol reflect cell (mostly plasma membrane) cholesterol? We have systematically quantitated this relationship for the first time. We found that ER cholesterol in resting human fibroblasts comprised approximately 0.5% of the cell total. The ER pool rose by more than 10-fold in less than 1 h as cell cholesterol was increased by approximately 50% from below to above its physiological value. The curve describing the dependence of ER on plasma membrane cholesterol had a J shape. Its vertex was at the ambient level of cell cholesterol and thus could correspond to a threshold. A variety of class 2 amphiphiles (e.g., U18666A) rapidly reduced ER cholesterol but caused only minor alterations in the J-curve. In contrast, brief exposure of cells to the oxysterol, 25-hydroxycholesterol, elevated and linearized the J-curve, increasing ER cholesterol at all values of cell cholesterol. This finding can explain the rapid action of oxysterols on cholesterol homeostasis. Other functions have also been observed to depend acutely on the level of plasma membrane cholesterol near its physiological level, perhaps reflecting a cholesterol-dependent structural or organizational transition in the bilayer. Such a physical transition could serve as a set-point above which excess plasma membrane cholesterol is transported to the ER where it would signal regulatory proteins to down-regulate its further accumulation. |
| Regulation of fatty acid and cholesterol metabolism by the AMP-activated protein kinase Hardie, D. G. (1992), Biochim Biophys Acta 1123(3): 231-8. |
| Regulation of fatty acid and cholesterol synthesis: co-operation or competition? Gibbons, G. F. (2003), Prog Lipid Res 42(6): 479-97. Abstract: Fatty acids and sterols originally evolved symbiotically as structural components of cell membranes. In some respects, control of their biosynthetic pathways reflects their mutual interdependence in defining changes in the physicochemical properties of the membranes in response to the changing internal and external cellular environments. In some tissues of higher animals, however, cholesterol and fatty acids have multifunctional roles. In particular, the liver synthesizes these lipids for export as multimolecular complexes in the form of micellar bile components and lipoproteins. Intrahepatic fatty acid and cholesterol synthesis is dependent upon the balance between hepatic output of these complexes and dietary input of fat and cholesterol. Thus physiological control of these synthetic processes is often co-ordinated at both the transcriptional and post-translational levels. On the other hand, changes in flux through major metabolic pathways, particularly during physiological transitions and as a result of genetic manipulation, affects substrate availability for these pathways. Under these circumstances, regulation reflects a compensatory response to ensure that flux through the lipid pathways remains unchanged. These regulatory changes can best be interpreted in terms of a Metabolic Control Analysis approach. In summary, flux through the fatty acid and cholesterol pathways reflects (a) cellular demand for these lipids, (b) a variable availability of substrates, (c) a combination of (a) and (b). |
| Regulation of fatty acid biosynthesis by intermediates of the cholesterol biosynthetic pathway Ku, E. C. (1996), Biochem Biophys Res Commun 225(1): 173-9. Abstract: The biosynthesis of cholesterol and fatty acid (FA) proceeds by independent pathways. Information is lacking on potential interaction that could provide feedback regulation between these pathways. In an attempt to search for a new approach to produce a dual effect on regulation of these two processes, we have identified mevalonate-5-diphosphate (MevPP) decarboxylase, an enzyme of the cholesterol biosynthesis pathway, the inhibition of which leads not only to the suppression of cholesterol but also FA biosynthesis. Mechanistic studies with Hep G2 cells using specific inhibitors for MevPP decarboxylase and related enzymes reveal that the inhibitory effect on FA biosynthesis is mainly due to the accumulation of MevPP, resulting from MevPP decarboxylase inhibition. The present study proposes a new mechanism through which interpathway regulation could take place between the cholesterol and FA cascades. |
| Regulation of fatty acid synthase expression by cholesterol in human cultured cells Kawabe, Y., R. Sato, et al. (1996), Biochem Biophys Res Commun 219(2): 515-20. Abstract: The regulation of fatty acid synthase (FAS) expression by sterols in a cultured human hepatoblastoma cell line, Hep G2, was studied. When cells were treated with compactin in a medium containing lipoprotein deficient serum, FAS mRNA level increased 1.6-fold. A squalene synthase inhibitor, TAN1607A, decreased both free and esterified cholesterol contents in Hep G2 cells and increased mRNA levels for FAS, HMG-CoA reductase, squalene synthase and LDL receptor. However, for the increment of FAS mRNA, a 10-fold higher concentration of this inhibitor was needed. These results demonstrate that the concentration of cellular cholesterol which regulates FAS expression is necessarily lower than the levels which regulate other sterol sensitive genes. FAS mRNA was also increased by an inhibitor of SREBP degradation as well as chenodeoxycholic acid. These results indicate that FAS mRNA expression is regulated by cholesterol and is mediated through SREBPs. The implications of the different modes of sterol regulation of FAS and LDL receptor expression are discussed. |
| Regulation of fecal bile acid excretion in male golden Syrian hamsters fed a cereal-based diet with and without added cholesterol Turley, S. D., D. K. Spady, et al. (1997), Hepatology 25(4): 797-803. Abstract: The objective of these studies was to investigate the comparative physiology and regulation of bile acid metabolism in the male Golden Syrian hamster by measuring the rate of fecal bile acid excretion and bile acid pool size in animals fed a cereal-based diet either alone, or with added cholesterol or cholestyramine. In group-housed hamsters fed only the plain diet fecal bile acid excretion in animals at 6, 10, and 15 weeks of age averaged 11.0, 8.0, and 6.9 mumol/d per 100 g body weight (bw), respectively. Pool size, measured by subtracting from the total amount of bile acid washed out over 12 hours of biliary diversion the amount of bile acid excreted in the stools over the same period, equalled 17.8 mumol/100 g bw in 15-week-old hamsters fed the plain diet. Hence, under basal conditions, these animals turned over about 38% of their bile acid pool daily. In hamsters fed a diet with 3% cholestyramine for 18 days, fecal bile acid excretion averaged 20.6 mumol/d per 100 g bw, and the pool size contracted to 5.8 mumol/100 g bw. In matching animals fed a diet containing 0.12% cholesterol for 30 days, hepatic cholesterol levels increased from 1.9 +/- 0.1 to 12.6 +/- 0.7 mg/g, fecal bile acid excretion increased marginally from 5.8 to 8.0 mumol/day per 100 g bw, while pool size was unchanged (16.6 mumol/100 g bw). When the cholesterol content of the diet was raised to 1.0%, hepatic cholesterol levels reached 66.5 +/- 2.6 mg/g, but bile acid excretion remained at 8 mumol/d per 100 g bw. These data define some of the basal features of bile acid metabolism in the hamster, and substantiate the view that the marked cholesterolemic response of this species may relate partly to a limited ability to convert dietary cholesterol to bile acid. |