| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Highly purified soybean protein is not hypocholesterolemic in rats but stimulates cholesterol synthesis and excretion and reduces polyunsaturated fatty acid biosynthesis Madani, S., S. Lopez, et al. (1998), J Nutr 128(7): 1084-91. Abstract: The specific effects of soybean protein on lipid metabolism were determined with highly purified soybean protein. At 5 wk of age, growing rats were fed diets containing 20% highly purified soybean protein or casein supplemented or not with 0.1% cholesterol for 2 mo. Plasma and liver lipid composition, fecal steroid excretion and several hepatic enzyme activities were measured. There were no significant dietary protein-related differences in plasma and liver cholesterol concentrations. When diets were cholesterol free, highly purified soybean protein stimulated fecal neutral and acidic steroid excretion associated with concomitantly higher hydroxy methylglutaryl CoA (HMG-CoA) reductase activity, but lower cholesterol 7alpha-hydroxylase activity. Soybean protein lowered the linoleate desaturation index 20:4(n-6)/18:2(n-6) in liver microsomal lipids and phospholipids. This may have been due to the reduced microsomal Delta6(n-6) desaturase activity in rats fed soybean protein, whereas Delta5(n-6) desaturase activity did not differ between groups fed the two proteins. Cholesterol supplementation (0.1%) did not affect plasma cholesterol but increased liver cholesterol and triacylglycerol concentrations and reduced HMG-CoA reductase activity; this latter effect was greatest in rats fed soybean protein. Cholesterol 7alpha-hydroxylase activity, however, was diminished only in rats fed casein. Desaturase activities, and particularly Delta5(n-6) activity, were lowered by cholesterol supplementation in rats fed both protein diets, including a significantly lower 20:4(n-6)/18:2(n-6) ratio in liver microsomal lipids and liver phospholipids. Thus although dietary proteins have no effect on serum cholesterol in rats, they affect enzyme activities involved in cholesterol metabolism and fatty acid desaturation. |
| Highly sensitive cholesterol assay with enzymatic cycling applied to measurement of remnant lipoprotein-cholesterol in serum Kishi, K., K. Ochiai, et al. (2002), Clin Chem 48(5): 737-41. Abstract: BACKGROUND: Remnant lipoprotein-cholesterol (RLP-C) concentrations in sera of healthy individuals are very low (0.080-0.437 mmol/L), making conventional cholesterol methods poorly suited to this purpose. We have developed a highly sensitive cholesterol assay (CD method) and applied it to the RLP-C assay. METHODS: The CD shuttled cholesterol reversibly between reduced and oxidized forms in the presence of thio-NAD and NADH. The production rate of thio-NADH correlated with the cholesterol concentration and was measured by the absorbance at 404/500 nm. This CD method was combined with an immunoaffinity separation procedure with specific monoclonal antibodies to apolipoprotein (apo) A1 and apo B-100 and used for RLP-C assay. Results were compared with a RLP-C method that uses cholesterol oxidase, peroxidase, and chromogenic substrate. RESULTS: The CD method could detect 0.10 x 10(-3) mmol/L cholesterol and was at least 5 times more sensitive than the conventional enzymatic method. Within- and between-day imprecision (as CVs) of the RLP-C assay with the CD method was <4%. Regression analysis of RLP-C assays with the new (y) and conventional (x) cholesterol methods yielded: y = 1.02x - 0.008 mmol/L (S(y/x) = 0.0065 mmol/L; r = 0.997; n = 297). CONCLUSIONS: Serum RLP-C can be measured by the CD method. The CD method may be useful for other assays that require sensitive cholesterol measurements in biological materials. |
| Highly stable phospholipid/cholesterol electrode coatings for amperometric monitoring of hydrophobic substances in flowing streams Wang, J. and Z. L. Lu (1990), Anal Chem 62(8): 826-9. Abstract: Composite electrode coatings based on a mixture of phosphatidylcholine and cholesterol offer remarkable mechanical stability under vigorous hydrodynamic conditions. The greatly improved stability (over single-domain phospholipid layers) is attained without compromising the attractive permselective response of lipid electrodes. The enhanced stability is attributed to changes in the fluidity/packing associated with the presence of cholesterol. Due to its high stability, simplicity, and fast and permselective response, the coated electrode seems well-suited for flow measurements of hydrophobic compounds. Parameters affecting the film permeability and the amperometric response are explored in the presence of numerous solutes of biological and pharmaceutical significance. Prevention of surface fouling (in the presence of surfactants) and applicability to selective assays of urine samples are illustrated. Such controlled access to the surface, based on solute polarity, greatly enhances the power of electrochemical flow detectors. |
| High-molecular-weight hydroxypropylmethylcellulose. A cholesterol-lowering agent Dressman, J. B., C. H. Adair, et al. (1993), Arch Intern Med 153(11): 1345-53. Abstract: BACKGROUND: We assessed the efficacy of a high-molecular-weight hydroxypropylmethylcellulose (K8515) as a cholesterol-lowering agent, the dose-response profile of its action, and the ability of adult subjects to tolerate its ingestion at effective doses. METHODS: These studies were conducted at the Clinical Research Center of The University of Michigan Hospitals, Ann Arbor. Efficacy was assessed in 10 normal and 12 mildly hyperlipidemic subjects in double-blind, randomized crossover trials of 1 and 2 weeks' duration, respectively. The dose-response profile was studied in 12 mildly hypercholesterolemic subjects in a nonrandomized control trial with doses given in escalating order. Tolerance was assessed by a questionnaire of adverse effects and bowel movement habits in all subjects. RESULTS: We found that 10 g of K8515 ingested in a prehydrated form three times a day with meals lowered total cholesterol levels by an average of 1.45 mmol/L (56 mg/dL) (32%) in normal subjects within 1 week. In two studies in subjects with mildly elevated cholesterol levels (with entry levels ranging from 5.35 mmol/L 207 mg/dL to 6.70 mmol/L 260 mg/dL), average reductions of 1.00 mmol/L (39 mg/dL) (18%) and 1.15 mmol/L (45 mg/dL) (20%) were observed within the same period. The effect was primarily due to a reduction in low-density lipoprotein cholesterol levels. Low-density lipoprotein levels in normal subjects were an average of 1.10 mmol/L (42 mg/dL) (38%) lower after a week of 10 g of K8515 three times a day with meals, and in the two studies in subjects with mild hyperlipidemia, the reductions in low-density lipoprotein levels after 1 week were 0.95 mmol/L (37 mg/dL) (23%) and 1.05 mmol/L (40 mg/dL) (25%). Although there was a tendency for high-density lipoprotein cholesterol levels to decrease, this was significant only in normal subjects. Decreases in cholesterol levels were not accompanied by any rise in triglyceride levels. Dose-response studies in those with mildly elevated cholesterol levels indicated that it is possible to achieve a 15% decrease in low-density lipoprotein cholesterol levels within 1 week at a dose of 6.7 g three times a day, with minimal adverse effects. CONCLUSION: These results suggest a role for high-molecular-weight hydroxypropylmethylcellulose in the clinical treatment of mild hypercholesterolemia. |
| High-monounsaturated fatty acid diets lower both plasma cholesterol and triacylglycerol concentrations Kris-Etherton, P. M., T. A. Pearson, et al. (1999), Am J Clin Nutr 70(6): 1009-15. Abstract: BACKGROUND: Low-fat diets increase plasma triacylglycerol and decrease HDL-cholesterol concentrations, thereby potentially adversely affecting cardiovascular disease (CVD) risk. High-monounsaturated fatty acid (MUFA), cholesterol-lowering diets do not raise triacylglycerol or lower HDL cholesterol, but little is known about how peanut products, a rich source of MUFAs, affect CVD risk. OBJECTIVE: The present study compared the CVD risk profile of an Average American diet (AAD) with those of 4 cholesterol-lowering diets: an American Heart Association/National Cholesterol Education Program Step II diet and 3 high-MUFA diets olive oil (OO), peanut oil (PO), and peanuts and peanut butter (PPB). DESIGN: A randomized, double-blind, 5-period crossover study design (n = 22) was used to examine the effects of the diets on serum lipids and lipoproteins: AAD 34% fat; 16% saturated fatty acids (SFAs), 11% MUFAs, Step II (25% fat; 7% SFAs, 12% MUFAs), OO (34% fat; 7% SFAs, 21% MUFAs), PO (34% fat; 7% SFAs, 17% MUFAs), and PPB (36% fat; 8% SFAs, 18% MUFAs). RESULTS: The high-MUFA diets lowered total cholesterol by 10% and LDL cholesterol by 14%. This response was comparable with that observed for the Step II diet. Triacylglycerol concentrations were 13% lower in subjects consuming the high-MUFA diets and were 11% higher with the Step II diet than with the AAD. The high-MUFA diets did not lower HDL cholesterol whereas the Step II diet lowered it by 4% compared with the AAD. The OO, PO, and PPB diets decreased CVD risk by an estimated 25%, 16%, and 21%, respectively, whereas the Step II diet lowered CVD risk by 12%. CONCLUSION: A high-MUFA, cholesterol-lowering diet may be preferable to a low-fat diet because of more favorable effects on the CVD risk profile. |
| High-performance liquid chromatographic determination of cholesterol and cholestanol in human serum by precolumn derivatization with 2-2-(isocyanate)ethyl-3-methyl-1,4-naphthoquinone combined with platinum catalyst reduction and electrochemical detection Nakajima, M., S. Yamato, et al. (1995), Biol Pharm Bull 18(12): 1762-4. Abstract: The precolumn derivatization reagent, 2-2-(isocyanate)ethyl-3-methyl- 1,4-naphthoquinone (IMQ) was applied to the simultaneous determination of cholesterol and cholestanol in human serum by HPLC with electrochemical detection. The compounds extracted with hexane from human serum, to which was added 1-eicosanol as an internal standard, were reacted with IMQ in acetone and converted into the corresponding carbamic acid esters. After chromatographic separation of the derivatives, they were reduced once in a platinum catalyst reduction column connected on-line, then quantified with an electrochemical detector in the oxidation mode. The detection limits at a signal-to-noise ratio of 3 were 6.6 pg (17 fmol) and 7.4 pg (19 fmol) for cholesterol and cholestanol, respectively in a 10 microliter injection volume. This method was successfully applied to the determination of free and total cholesterol and total cholestanol in normal human serum, and the concentrations of free and total cholesterol were compared with those obtained by an enzymatic method. |
| High-performance liquid chromatography analysis of cholesterol linoleate hydroperoxide in oxidized low density lipoproteins: calibration by conjugated diene internal standard Handelman, G. J. (1999), Methods Enzymol 300: 43-50. Abstract: The cholesterol linoleate hydroperoxides formed in LDL after oxidant stress are measured by HPLC, with UV detection at 234 nm. Calibration is performed with a conjugated diene internal standard. This internal standard is synthesized by the transesterification of the methyl ester of conjugated diene linoleic acid with a long-chain alcohol, such as arachidyl alcohol (C20). Different long-chain alcohols can be used during the transesterification, to achieve internal standards with variable HPLC retention times. The method allows measurement of cholesterol linoleate hydroperoxide in LDL very early during attack with Cu2+ or other initiator, so that the kinetics of antioxidant loss and hydroperoxide formation can be concurrently monitored. |
| High-resolution mapping of the frequency of lipid deposits in thoracic aortae from cholesterol-fed and heritable hyperlipidaemic rabbits Forster, B. A., Q. Javed, et al. (1996), Atherosclerosis 120(1-2): 249-53. |
| High-resolution maps of the murine Chromosome 2 region containing the cholesterol gallstone locus, Lith1 Bouchard, G., H. M. Nelson, et al. (1999), Mamm Genome 10(11): 1070-4. Abstract: The Lith1 region on Chromosome (Chr) 2 contains a gene that markedly affects the prevalence of cholesterol gallstones in inbred mice. We report the high-resolution genetic and radiation hybrid maps of the chromosomal region surrounding Lith1, using three resources: a DNA panel from 188 progeny from two reciprocal backcrosses between C57BL/6 and Mus spretus inbred strains; 423 progeny of an N4 generation from backcrossing the susceptible C57L/J alleles at Lith1 into the resistant AKR/J strain; and the newly developed hamster-mouse T31 radiation hybrid panel. We mapped 17 microsatellite markers in the D2Mit182 to D2Mit14 region and two candidate genes for Lith1, the canalicular bile salt export pump (Bsep) also known as sister of P-glycoprotein (Spgp) and the low-density-lipoprotein-receptor-related gene megalin (Gp330). Both genetic maps were in agreement and ordered the microsatellite markers into a 10.4 +/- 1.5 cM region. The high-resolution physical map revealed ordering of microsatellite markers and relative distances between markers in almost complete agreement with the genetic maps. Mapping of Bsep revealed its location on Chr 2, homologous to the human chromosomal position (Nature Genet 20, 233-238, 1998). The radiation hybrid results also provided the highest resolution of the area containing the two candidate genes, which both mapped in the Lith1 region with close linkage, being separated by a distance of only 15 cR(3000). The total radiation hybrid map length of the region between D2Mit182 and D2Mit14 was 326 cR(3000), suggesting that 31 cR(3000) is equivalent to 1 cM in this region of Chr 2. |
| High-risk elderly patients PROSPER from cholesterol-lowering therapy Collins, R. and J. Armitage (2002), Lancet 360(9346): 1618-9. |
| High-sensitive chemiluminescent assay for cholesterol Chamoin, M. C., M. Charbonnier, et al. (1994), Biochim Biophys Acta 1210(2): 151-6. Abstract: Chemiluminescent measurement of cholesterol can be performed in various biological tissues and fluids. The method described in this study has a sensitivity of 54 pmol. The tissue samples used for the determination of cholesterol can be reduced to as little as 1 mg and assay can be performed on diluted biological fluids, allowing sampling of plasma or serum as little as 5 microliters. Cholesterol is solubilized in sodium cholate and aliquots are added to a reaction mixture containing cholesterol oxidase, luminol and peroxidase. Cholesterol oxidase, in the presence of cholesterol yields H2O2 which produces light in presence of luminol and peroxidase. Emitted light is quantified at a wavelength of 420 nm by means of a photomultiplier. Optimal conditions of the assay were determined and examples of cholesterol determinations, in blood plasma and nervous tissues, are presented. |
| Histologic, hematologic, and biochemical characteristics of apo E-deficient mice: effects of dietary cholesterol and phytosterols Moghadasian, M. H., L. B. Nguyen, et al. (1999), Lab Invest 79(3): 355-64. Abstract: In this study, we examined the effects of a "Western-type" diet containing 9% (w/w) fat and 0.15% (w/w) cholesterol, in the presence or absence of 2% (w/w) phytosterol mixture over an 18-week period in apolipoprotein E-deficient mice. Addition of phytosterols to the high cholesterol diet was associated with normalization of the depressed hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity (from 22.3+/-6.3 to 55.4+/-19.9 pmol/mg protein/minutes, p < 0.05). This finding was associated with a significant decrease in plasma and hepatic cholesterol concentrations compared with animals fed the high cholesterol diet without phytosterols (33.3+/-5.0 versus 19.2+/-6.2 pmol/mg protein, p < 0.05). The activities of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase were comparable between the two groups of mice. Urinalyses and hematologic data were comparable between the two groups except for significantly lower platelet counts in the phytosterol-treated animals (681.6+/-118.9 versus 857.1+/-185.4 x10(9)/L, p < 0.05). The phytosterol-treated animals had significantly (p < 0.05) less fragile erythrocytes when exposed to 0.08, 0.07, or 0.05 M NaCl compared with cholesterol-fed mice. The consumption of the Western-type diet was associated with the development of xanthomatous skin lesions in 33% of the cholesterol-fed animals, but in none of the phytosterol-treated animals. Histologic examination revealed oil red O-negative vacuolation in liver and kidney parenchymal cells of the cholesterol-fed group, but not in the phytosterol-treated mice. Arrested spermatogenesis and atrophy of seminiferous tubules were observed, to a variable extent, in both groups of animals. We conclude that addition of the phytosterol mixture (2% w/w) to a Western-type diet in apolipoprotein E-deficient mice significantly decreases plasma and hepatic cholesterol concentrations, increases hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity, and prevents cutaneous xanthomatosis and vacuolation in the parenchymal cells of kidneys and livers. |
| Histological evaluation of the intrahepatic biliary tree in intrahepatic cholesterol stones, including immunohistochemical staining against apolipoprotein A-1 Ohta, T., T. Nagakawa, et al. (1993), Hepatology 17(4): 531-7. Abstract: Apolipoprotein A-1 is known to be one of inhibiting factors of cholesterol nucleation in bile, and decreased activity of apolipoprotein A-1 is considered to predispose cholesterol-supersaturated bile to formation of cholesterol crystals. To study the pathogenesis of the intrahepatic formation of cholesterol stones, we examined surgically resected liver specimens from six patients with intrahepatic cholesterol stones and compared the characteristic histopathological features with those of intrahepatic calcium bilirubinate stones, using morphological examination and immunohistochemical staining against apolipoprotein A-1. Morphologically, in all six patients with cholesterol stones the severity of chronic proliferative cholangitis with proliferation of the mucus-producing glandular elements in the walls of the large bile duct or periductal tissues was less extensive than that seen with calcium bilirubinate stones, and cholesterol crystals had formed in the septal and interlobular bile ducts. Immunohistochemically, unlike the normal liver and calcium bilirubinate stone-containing lobes, the hepatocytes and the epithelial lining of the bile ducts and peribiliary glands of the cholesterol stone-containing lobes did not react completely (some of the epithelial cells reacted only faintly) with apolipoprotein A-1 antibody. These findings suggest that an abundance of mucous substance and bacterial infection of the biliary tree may not be necessary for the formation of cholesterol stones, compared with findings in cases of calcium bilirubinate stones. We suggest that cholesterol crystals may be produced in the septal and interlobular bile ducts in the microenvironment of cholesterol-supersaturated bile and decreased activity of apolipoprotein A-1. |
| Histopathologic study of the temporal bones and Eustachian tubes of children with cholesterol granuloma Miura, M., I. Sando, et al. (2002), Ann Otol Rhinol Laryngol 111(7 Pt 1): 609-15. Abstract: Six temporal bone-eustachian tube (ET) specimens with cholesterol granuloma (CG), obtained from 6 children 6 months to 15 years of age, were studied histopathologically to obtain further information about the pathogenesis of CG. We observed CG in the mastoid air cells in 5 ears, the mastoid antrum in 1 ear, the aditus ad antrum in 2 ears, and the epitympanum in 1 ear. All 6 cases exhibited a large amount of remaining mesenchyme that was in continuity with the hematopoietic bone marrow in the locations in which CG was present. All cases demonstrated otitis media with effusion and inflammation of the ET. Apparent morphological abnormalities of the ET and its associated structures, including hypoplastic ET cartilage and an abnormal tensor veli palatini muscle, were noted in 3 of the 6 cases. Furthermore, the posterior cartilaginous portion of the ET that includes its narrowest portion was completely filled with effusion in 2 of the 3 cases with the ET anomaly. The findings obtained were compared with data from age-matched control cases. Our results suggest that the source of erythrocytes in the remaining mesenchyme is the hematopoietic bone marrow. The pathogenesis of CG in children is likely promoted by ET dysfunction resulting in failure of ventilation of the middle ear. |
| Histopathology of arterial lesions in LPA transgenic mice on cholesterol-enriched chow Svindland, A., K. Berg, et al. (2000), Atherosclerosis 153(2): 349-54. Abstract: The aortic root from 21 LPA transgenic mice and 18 control litter mates on cholesterol enriched chow were studied histologically for the presence of atherosclerotic lesions. Serial sections were cut and the total area of the lesions was measured by use of computerised image analysis. Lipid staining lesions were found in 17 aortas of the transgenic mice and were five times more common than in the controls. Foam cell lesions were the only type of lesion in 12 of the aortas from transgenic animals, while five animals had developed fibrofatty lesions. Immunostaining revealed monocytes/macrophages on the endothelial surface, and in the subendothelial space of foam cell lesions. In fibrofatty lesions, spindle shaped cells formed a cap around the lipid core. This study supports the view that transgenic mice expressing human apolipoprotein (a) on a high fat and cholesterol diet, are more susceptible to aortic lesions than control mice and develop early atherosclerotic lesions comparable to lesions in man. Aminoguanidin in the drinking water had no effect on the aortic lesions, but lesion size was significantly, negatively correlated with plasma glucose concentration. |
| Historical aspects of cholesterol value by various analytical methods Kitamura, M. (1991), Rinsho Byori 39(5): 495-500. Abstract: Chemical analysis, which had been used for routine test until enzymatic analysis was developed by Richmond in 1973, gave 10% or much higher systematic error on serum cholesterol level compared to orthodox reference method. Direct analysis without deproteinization, which was used widely in the 1960's because of ease of use, gave even more erroneous value caused by interference depending on each sample. Although cholesterol oxidase method is good, its reliability depends on reagent kit or instrument. Therefore, in reality, the method shows unexpected large interlaboratory differences. At this stage it is impossible to discuss the meaning of 10-20 mg/dl difference on serum cholesterol level. |
| Historical development of the cholesterol-atherosclerosis concept Epstein, F. H. (1990), Ther Umsch 47(6): 435-42. Abstract: The development of the cholesterol hypothesis to the cholesterol theory, as related to atherogenesis, is followed in chronological sequence. The major milestones in terms of chemical pathology of the lesions, clinical observations on serum cholesterol levels in patients with coronary heart disease, lipoprotein research, epidemiological investigations and prevention of diseases due to atherosclerosis are described within three time periods: from the 19th till the beginning of the 20th century, the years between the two World Wars and the last 40 years. A total picture emerges which assigns to cholesterol and its lipoprotein carriers a key role in the origins and progression of atherosclerosis. These causal relationships have opened the way to the prevention of the disease, supported by intervention studies aimed at reduction of serum cholesterol levels. |
| History and development of plant sterol and stanol esters for cholesterol-lowering purposes Thompson, G. R. and S. M. Grundy (2005), Am J Cardiol 96(1A): 3D-9D. Abstract: Plant stanol esters provide a novel approach to lowering plasma low-density lipoprotein (LDL) cholesterol by dietary means. Their development was preceded by a long period of research into the cholesterol-lowering properties of plant sterols and, recently, plant stanols. Both classes of compound competitively inhibit the absorption of cholesterol and thus lower its level in plasma. Initial impressions were that stanols were more effective and safer than sterols, but the negative outcome of a study led to the recognition that the lipid solubility of free stanols was very limited. This was overcome by esterifying them with fatty acids, with the resultant stanol esters being freely soluble in fat spreads. This led to the launch of Benecol (margarine; Raisio Group, Raisio, Finland) in 1995. The coincident publication of the year-long North Karelia study conclusively demonstrated the long-term LDL-lowering efficacy of plant stanol esters. Variables that might influence the efficacy of stanol esters include dose, frequency of administration, food vehicle in which the stanol ester is incorporated, and background diet. The effective dose is 1 to 3 g/day, expressed as free stanol, which, in placebo-controlled studies, decreased LDL cholesterol by 6% to 15%. This effect is maintained, appears to be similar with once-daily or divided dosage, and is independent of the fat content of the food vehicle. Short-term studies suggest that equivalent amounts of plant sterol and stanol esters are similarly effective in lowering LDL, the main difference being that plasma plant sterol levels increase on plant sterols and decrease on plant stanols. The clinical significance of these changes remains to be determined. |
| HL-004, the ACAT inhibitor, prevents the progression of atherosclerosis in cholesterol-fed rabbits Asami, Y., I. Yamagishi, et al. (1998), Life Sci 62(12): 1055-63. Abstract: HL-004, N-(2,6-diisopropylphenyl) tetradecylthioacetamide, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was evaluated concerning the possible prevention of hyperlipidemia and atherosclerosis in 1% cholesterol-fed rabbits. HL-004 (0.2, 5 and 25 mg/kg) was orally administered once a day for 12 weeks. HL-004 inhibited the rise of total serum cholesterol at a dose of 5 mg/kg and over. In the thoracic aorta, HL-004 at the doses of 5 mg/kg and 25 mg/kg reduced the total cholesterol content by 56.3% and 84.2% compared with control, and decreased ACAT activity, dose-dependently. HL-004 also attenuated the development of aortic lesions. The area of atherosclerotic lesions was reduced by 30.3% with 5 mg/kg of HL-004 and 100% with 25 mg/kg. In this study, we suggest that the main reason for HL-004 preventing the progression of atherosclerosis is its hypocholesterolemic effect due to the inhibition of cholesterol absorption in the intestine. |
| HLH106, a Drosophila sterol regulatory element-binding protein in a natural cholesterol auxotroph Rosenfeld, J. M. and T. F. Osborne (1998), J Biol Chem 273(26): 16112-21. Abstract: In mammalian cells, sterol regulatory element-binding proteins (SREBPs) coordinate metabolic flux through the cholesterol and fatty acid biosynthetic pathways in response to intracellular cholesterol levels. We describe experiments that evaluate the functional equivalence of mammalian SREBPs and the insect homologue of SREBP-1a, HLH106, in both mammalian and insect cell culture systems. HLH106 binds to both palindromic E-boxes and direct repeat sterol regulatory elements (SREs) efficiently, suggesting that it has a dual DNA binding specificity similar to the mammalian proteins. The amino-terminal "mature" protein activates transcription from mammalian SREs in both mammalian and Drosophila tissue culture cells. Additionally, HLH106 also requires a ubiquitous regulatory co-activator to efficiently activate transcription from mammalian SREs. These properties are shared with its mammalian counterparts. When expressed in mammalian cells, the carboxyl-terminal portion also localizes to perinuclear membranes similar to mammalian SREBPs. Furthermore, membrane-bound HLH106 is proteolytically processed in response to intracellular sterol levels in mammalian cells in an SREBP cleavage-activating protein-stimulated fashion. The presence of an SREBP homologue in Drosophila whose processing is regulated by intracellular sterol levels when expressed in mammalian cells suggests that related processing machinery exists in insect cells. This is notable, since insects are reportedly incapable of de novo sterol biosynthesis. |