The Experts below are selected from a list of 195 Experts worldwide ranked by ideXlab platform
Tatu A Miettinen - One of the best experts on this subject based on the ideXlab platform.
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cholesterol and glucose metabolism and recurrent cardiovascular events among the elderly a prospective study
Journal of the American College of Cardiology, 2006Co-Authors: Timo E Strandberg, Reijo S Tilvis, Kaisu H Pitkala, Tatu A MiettinenAbstract:OBJECTIVES The aim of this research was to evaluate the prognostic value of cholesterol absorption assessed with the serum Cholestanol-to-cholesterol concentration ratio (lower level reflects decreased cholesterol absorption) among elderly cardiovascular patients (DEBATE [Drugs and Evidence-Based Medicine in the Elderly] study). BACKGROUND The components of the metabolic syndrome have been unexpectedly associated with better prognosis among elderly cardiovascular patients. On the other hand, a metabolic syndrome-type state is characterized by high synthesis and decreased absorption of cholesterol. METHODS This was a prospective cohort study of home-dwelling individuals age 75 years and older with cardiovascular diseases (247 women, 129 men) recruited from the community. Main outcome measure was multivariate-adjusted time to 3.4-year mortality and recurrent major cardiovascular events. RESULTS Serum total and low-density lipoprotein cholesterol levels did not predict outcome. Instead, the mortality risk (64 deaths) increased with increasing levels of Cholestanol-to-cholesterol ratio. Patients in the 2nd, 3rd, and 4th quartiles had a relative hazard ratio (HR) for death of 2.54 (95% confidence interval [CI] 1.05 to 6.12), 2.48 (95% CI 1.03 to 6.00), and 3.53 (95% CI 1.52 to 8.19) compared with the lowest quartile, even though 50% of individuals in the lowest Cholestanol quartile had metabolic syndrome or diabetes. In multivariate models, the lowest Cholestanol ratio quartile was independently associated with lower mortality (relative HR, 0.37, 95% CI 0.17 to 0.81), and with fewer major cardiovascular events (115 events, relative HR, 0.59, 95% CI 0.35 to 0.98). CONCLUSIONS Low cholesterol absorption was associated with fewer recurrent cardiovascular events, and with better survival in elderly patients despite frequent abnormalities of glucose metabolism.
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polymorphisms in the abcg5 and abcg8 genes associate with cholesterol absorption and insulin sensitivity
Journal of Lipid Research, 2004Co-Authors: Helena Gylling, Maarit Hallikainen, Jussi Pihlajamäki, Jyrki J. Ågren, Markku Laakso, Radhakrishnan A. Rajaratnam, Rainer Rauramaa, Tatu A MiettinenAbstract:The roles of polymorphisms of the sitosterolemia genes ABCG5 and ABCG8 in the regulation of cholesterol metabolism and insulin sensitivity were studied in mildly hypercholesterolemic noncoronary subjects (n = 263, 144 menand 119 women) divided into tertiles by baseline serum Cholestanol-to-cholesterol ratio (≤118.3 and ≥147.7 10 2 × mmol/mol cholesterol), a surrogate marker of cholesterol absorption efficiency. The lowest Cholestanol tertile was associated with high body mass index (BMI), plasma glucose, serum insulin and triglycerides, and cholesterol synthesis markers (cholestenol, desmosterol, lathosterol) and low HDL cholesterol and cholesterol absorption markers (campesterol, sitosterol) (P <0.01 for all). The 19H allele of the ABCG8 gene accumulated in the lowest Cholestanol tertile (P < 0.001) and was associated with low total and LDL cholesterol and absorption markers and with high synthesis markers (P < 0.05 for all). The 604E allele of the ABCG5 gene in men was associated with high BMI, plasma insulin, low serum sitosterol, and high serum cholestenol levels (P < 0.05 for all). In a subgroup of 71 men, the 604E allele was associated with insulin resistance measured with the hyperinsulinemic euglycemic clamp. In conclusion, low cholesterol absorption efficiency was associated with characteristics of the metabolic syndrome. Low serum cholesterol and cholesterol absorption were linked to the D19H polymorphism of the ABCG8 gene, and characteristics of the insulin resistance syndrome in men were linked with the Q604E polymorphism of the ABCG5 gene.
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Polymorphisms in the ABCG5 and ABCG8 genes associate with cholesterol absorption and insulin sensitivity
Journal of lipid research, 2004Co-Authors: Helena Gylling, Maarit Hallikainen, Jussi Pihlajamäki, Jyrki J. Ågren, Markku Laakso, Radhakrishnan A. Rajaratnam, Rainer Rauramaa, Tatu A MiettinenAbstract:The roles of polymorphisms of the sitosterolemia genes ABCG5 and ABCG8 in the regulation of cholesterol metabolism and insulin sensitivity were studied in mildly hypercholesterolemic noncoronary subjects (n = 263, 144 menand 119 women) divided into tertiles by baseline serum Cholestanol-to-cholesterol ratio (≤118.3 and ≥147.7 10 2 × mmol/mol cholesterol), a surrogate marker of cholesterol absorption efficiency. The lowest Cholestanol tertile was associated with high body mass index (BMI), plasma glucose, serum insulin and triglycerides, and cholesterol synthesis markers (cholestenol, desmosterol, lathosterol) and low HDL cholesterol and cholesterol absorption markers (campesterol, sitosterol) (P
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noncholesterol sterols and cholesterol lowering by long term simvastatin treatment in coronary patients relation to basal serum Cholestanol
Arteriosclerosis Thrombosis and Vascular Biology, 2000Co-Authors: Tatu A Miettinen, Timo E Strandberg, Helena GyllingAbstract:Abstract —Coronary patients with low baseline ratios of serum Cholestanol and plant sterols to cholesterol (indicating low cholesterol absorption) but not those with high ratios (high absorption) experienced reduced recurrences of coronary events during simvastatin treatment in the Scandinavian Simvastatin Survival Study. Thus, in the present study, serum cholesterol, its precursor sterols (reflecting cholesterol synthesis), plant sterols (campesterol and sitosterol), and Cholestanol were measured before and during a 5-year period of placebo treatment (n=433) and simvastatin treatment (n=434) in patients from a subgroup of the Scandinavian Simvastatin Survival Study to determine whether changes in cholesterol synthesis and serum levels were related to cholesterol absorption. Serum cholesterol level was unchanged, the ratios of cholesterol precursor sterols to cholesterol were decreased, and the ratios of plant sterols to cholesterol were increased in relation to increasing baseline ratios of Cholestanol quartiles. The latter predicted 5-year ratios and simvastatin-induced reductions of the precursor sterols, with the lowering of the ratios (cholesterol synthesis reduction) being almost twice higher in the lowest versus the highest quartile. The ratios of plant sterols, especially campesterol, to cholesterol were markedly increased during simvastatin treatment, mostly in subjects with the highest baseline Cholestanol quartiles. Simvastatin reduced serum cholesterol more ( P =0.003) in the lowest versus the highest Cholestanol quartile during the 5-year treatment period. The results show for the first time that baseline cholesterol metabolism, measured by serum noncholesterol sterols, predicts the effectiveness of simvastatin in reducing cholesterol synthesis and serum levels of cholesterol. The drug suppresses the synthesis of cholesterol markedly more effectively in subjects with high than with low baseline synthesis but reduces respective serum cholesterol levels less markedly than synthesis. Subjects with high cholesterol absorption and low synthesis may need a combination therapy to lower more effectively their serum cholesterol levels and prevent an increase in the levels of plant sterols.
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serum Cholestanol cholesterol precursors and plant sterols in different inflammatory bowel diseases
Digestion, 1996Co-Authors: Kalle Hakala, M Vuoristo, Tatu A MiettinenAbstract:The role of cholestasis and ileal dysfunction on sterol metabolism was studied in 79 patients with inflammatory bowel diseases (IBDs) and in 23 irritable bowel syndrome (IBS) controls by determining serum sterol/cholesterol proportions. The sterols included cholesterol precursors (Δ8-cholestenol, desmo-sterol and lathosterol), markers of cholesterol synthesis, Cholestanol and plant sterols (campesterol and sitosterol), markers of cholesterol absorption and biliary secretion. The IBD patients were subgrouped into distal ulcerative colitis (dUC, n = 21), pancolitis (pUC, n = 29), ileal Crohn’s disease (iCD, n = 20) and colonic Crohn’s disease (cCD, n = 9). The Cholestanol proportions were increased in the 3 colonic IBD groups, up to two times in cCD patients and seven times in a case with clinically overt primary sclerosing cholangitis, but were within the control IBS levels in the patients with iCD. The sitosterol, but not campesterol, proportion was significantly increased only in the pUC group. In the iCD group only the serum precursor sterol proportions, especially those for Δ8-cholestenol and lathosterol, were elevated probably due to ileal dysfunction induced bile acid malabsorption and compensatorily increased cholesterol synthesis. In conclusion, the findings suggest that the increased Cholestanol proportion in colonic IBD is determined mainly by impaired biliary elimination of this sterol, while in ileal affision the dominating change in sterol balance is activated cholesterol synthesis. Thus increased serum Cholestanol is a novel finding in colonic IBD, apparently indicating the presence of subclinical cholestasis in a marked number (20-50%) of IBD patients.
Ingemar Bjorkhem - One of the best experts on this subject based on the ideXlab platform.
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Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum
Journal of Biological Chemistry, 2017Co-Authors: Natalia Mast, Ingemar Bjorkhem, Kyle W. Anderson, Illarion V Turko, Curtis Tatsuoka, Yong Li, Irina A PikulevaAbstract:Abstract Cytochrome P450 27A1 (CYP27A1 or sterol 27-hydroxylase) is a ubiquitous, multifunctional enzyme catalyzing regio- and stereo-specific hydroxylation of different sterols. In humans, complete CYP27A1 deficiency leads to cerebrotendinous xanthomatosis or nodule formation in tendons and brain (preferentially in the cerebellum) rich in cholesterol and Cholestanol, the 5α-saturated analog of cholesterol. In Cyp27a1-/- mice, xanthomas are not formed, despite a significant Cholestanol increase in the brain and cerebellum. The mechanism behind Cholestanol production has been clarified, yet little is known about its metabolism, except that CYP27A1 might metabolize Cholestanol. It also is unclear why CYP27A1 deficiency results in preferential Cholestanol accumulation in the cerebellum. We hypothesized that Cholestanol might be metabolized by CYP46A1, the principal cholesterol 24-hydroxylase in the brain. We quantified sterols along with CYP27A1 and CYP46A1 in mouse models (Cyp27a1-/-, Cyp46a1-/-, Cyp27a1-/- Cyp46a1-/-, and two wild type strains) and human brain specimens. In vitro experiments with purified P450s were conducted as well. We demonstrate that CYP46A1 is involved in Cholestanol removal from the brain, and that several factors contribute to the preferential increase in Cholestanol in the cerebellum arising from CYP27A1 deficiency. These factors include: (i) low cerebellar abundance of CYP46A1 and high cerebellar abundance of CYP27A1, whose lack likely selectively increases the cerebellar Cholestanol production; (ii) spatial separation in the cerebellum of cholesterol/Cholestanol-metabolizing P450s from a pool of metabolically available Cholestanol; and (iii) weak cerebellar regulation of cholesterol biosynthesis. We identified a new physiological role of CYP46A1, an important brain enzyme and cytochrome P450 that could be activated pharmacologically.
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A Novel Pathway for Biosynthesis of Cholestanol with 7a-Hydroxylated C27-Steroids as Intermediates, and Its Importance for the Accumulation of Cholestanol in Cerebrotendinous Xanthomatosis
2016Co-Authors: Sverre Skrede, Ingemar Bjorkhem, Marie S. Buchmann, G Hopen, O FausaAbstract:A mixture of 7a-3H- and 4-'4C-labeled cholesterol was admin-istered intravenously to rats. Cholestanol with 20-30 % lower ratio between 3H and '4C than in cholesterol could be isolated from different organs. In a healthy human control, Cholestanol isolated from feces had a 3H/'4C ratio which was 28 % lower than in administered cholesterol. Cholesterol and coprostanol reisolated in these experiments had the same ratio between 3H and 14C as in the precursor. A previously unknown pathway for formation of Cholestanol, involving 7a-hydroxylated inter-mediates, may explain these results. Under normal conditions, this pathway is responsible for at most 30 % of the Cholestanol synthesized from cholesterol. Intravenous administration of the 7a-3H- and 4-'4C-labeled cholesterol to a patient with cerebrotendinous xanthomatosi
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on the mechanism of accumulation of Cholestanol in the brain of mice with a disruption of sterol 27 hydroxylase
Journal of Lipid Research, 2010Co-Authors: Ann Bavner, Eran Leitersdorf, Marjan Shafaati, Magnus Hansson, Maria Olin, Shoshi Shpitzen, Vardiella Meiner, Ingemar BjorkhemAbstract:The rare disease cerebrotendinous xanthomatosis (CTX) is due to a lack of sterol 27-hydroxylase (CYP27A1) and is characterized by Cholestanol-containing xanthomas in brain and tendons. Mice with the same defect do not develop xanthomas. The driving force in the development of the xanthomas is likely to be conversion of a bile acid precursor into Cholestanol. The mechanism behind the xanthomas in the brain has not been clarified. We demonstrate here that female cyp27a1−/− mice have an increase of Cholestanol of about 2.5- fold in plasma, 6-fold in tendons, and 12-fold in brain. Treatment of cyp27a1−/− mice with 0.05% cholic acid normalized the Cholestanol levels in tendons and plasma and reduced the content in the brain. The above changes occurred in parallel with changes in plasma levels of 7α-hydroxy-4-cholesten-3-one, a precursor both to bile acids and Cholestanol. Injection of a cyp27a1−/− mouse with 2H7-labeled 7α-hydroxy-4-cholesten-3-one resulted in a significant incorporation of 2H7-Cholestanol in the brain. The results are consistent with a concentration-dependent flux of 7α-hydroxy-4-cholesten-3-one across the blood-brain barrier in cyp27a1−/− mice and subsequent formation of Cholestanol. It is suggested that the same mechanism is responsible for accumulation of Cholestanol in the brain of patients with CTX.
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on the mechanism of cerebral accumulation of Cholestanol in patients with cerebrotendinous xanthomatosis
Journal of Lipid Research, 2007Co-Authors: Ute Panzenboeck, Magnus Hansson, Ulla Andersson, Wolfgang Sattler, Steve Meaney, Ingemar BjorkhemAbstract:The most serious consequence of sterol 27-hydroxylase deficiency in humans [cerebrotendinous xanthomatosis (CTX)] is the development of Cholestanol-containing brain xanthomas. The Cholestanol in the brain may be derived from the circulation or from 7alpha-hydroxylated intermediates in bile acid synthesis, present at 50- to 250-fold increased levels in plasma. Here, we demonstrate a transfer of 7alpha-hydroxy-4-cholesten-3-one across cultured porcine brain endothelial cells (a model for the blood-brain barrier) that is approximately 100-fold more efficient than the transfer of Cholestanol. Furthermore, there was an efficient conversion of 7alpha-hydroxy-4-cholesten-3-one to Cholestanol in cultured neuronal and glial cells as well as in monocyte-derived macrophages of human origin. It is concluded that the continuous intracellular production of Cholestanol from a bile acid precursor capable of rapidly passing biomembranes, including the blood-brain barrier, is likely to be of major importance for the accumulation of Cholestanol in patients with CTX. Such a mechanism also fits well with the observation that treatment with chenodeoxycholic acid, which normalizes the level of the bile acid precursor, results in a reduction of Cholestanol-containing xanthomas even in the brain.
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mechanism of accumulation of cholesterol and Cholestanol in tendons and the role of sterol 27 hydroxylase cyp27a1
Arteriosclerosis Thrombosis and Vascular Biology, 2002Co-Authors: Sara Von Bahr, Irina A Pikuleva, Tomas Movin, Nikos Papadogiannakis, Per Ronnow, Ulf Diczfalusy, Ingemar BjorkhemAbstract:Objective — Tendon xanthomas are deposits of lipids and connective tissue commonly found in hypercholesterolemic patients. Macrophages are likely to be responsible for the lipid accumulation. Normolipidemic patients with the rare disease cerebrotendinous xanthomatosis, lacking the enzyme sterol 27-hydroxylase (CYP27A1), develop prominent xanthomas in tendons and brain containing both Cholestanol and cholesterol, with a Cholestanol:cholesterol ratio higher than that in the circulation. Because of its ability to convert cholesterol into polar metabolites that leave the cells faster, CYP27A1 has been suggested to be an antiatherogenic enzyme. The hypothesis was tested that tendons contain CYP27A1 that may be of importance for the normal efflux of both steroids. Methods and Results — Western blotting and combined gas chromatography-mass spectrometry showed that human tendons contain significant amounts of CYP27A1 and its product, 27-hydroxycholesterol. Immunohistochemistry showed that CYP27A1 is present in macrophages and tenocytes. The tendons also contained Cholestanol, with a Cholestanol:cholesterol ratio slightly higher than that in the circulation. Recombinant human CYP27A1, and cultured human macrophages containing this enzyme, had similar activity toward cholesterol and Cholestanol. After loading of macrophages with labeled cholesterol and Cholestanol, there was an efflux of these steroids in both unmetabolized and 27-oxygenated form, resulting in a significant cellular accumulation of Cholestanol compared with cholesterol. Conclusion — The results are consistent with the possibility that CYP27A1 is of importance for the efflux of both cholesterol and Cholestanol from tendons.
Helena Gylling - One of the best experts on this subject based on the ideXlab platform.
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serum plant sterols Cholestanol and cholesterol precursors associate with histological liver injury in pediatric onset intestinal failure
The American Journal of Clinical Nutrition, 2014Co-Authors: Annika Mutanen, Helena Gylling, Markku Nissinen, Jouko Lohi, Paivi Heikkila, Mikko P PakarinenAbstract:Background: Increased serum concentrations of plant sterols, including stigmasterol, during parenteral nutrition (PN) have been linked with serum biochemical signs of intestinal failure–associated liver disease (IFALD), whereas clinical data on their correlation to histologic liver injury have been limited. Objective: We studied interrelations between serum noncholesterol sterols and histologic liver injury in pediatric-onset intestinal failure (IF). Design: Serum plant sterols (stigmasterol, avenasterol, sitosterol, and campesterol), Cholestanol, and cholesterol precursors (cholestenol, lathosterol, and desmosterol) were measured in 50 IF patients at a median age 7.3 y and in 86 matched controls. Forty patients underwent liver biopsies. Sixteen patients had been receiving PN for 45 mo, and 34 patients had received PN for 9.1 mo but had not received PN for 5.4 y. Results: Serum plant sterols were higher in patients who were currently receiving PN than in controls and were related to conjugated bilirubin (r = 0.799–0.541, P , 0.05). During PN, the ratio of serum stigmasterol to cholesterol was 3.3-fold higher in patients with portal inflammation, and the ratio of avenasterol to cholesterol was 3.9-fold higher in patients with cholestasis (P , 0.05 for both). Ratios of stigmasterol and avenasterol to cholesterol were correlated with portal inflammation (r = 0.549–0.510, P , 0.05), cholestasis (r = 0.501–0.491, P = 0.048–0.053), and serum bile acids (r = 0.591–0.608, P , 0.05). The median (IQR) ratio of serum Cholestanol to cholesterol was higher during (269 1003 mg/mg cholesterol; 203–402 1003 mg/mg cholesterol) than after (175 1003 mg/mg cholesterol; 156–206 1003 mg/mg cholesterol; P , 0.001) weaning off PN and was correlated with cholestasis (r = 0.428), portal inflammation (r = 0.511), and fibrosis (r =0 .323,P , 0.05 for all). After weaning off PN, ratios of cholestenol and lathosterol to cholesterol were .2-fold higher in patients with persistent liver steatosis than in those without steatosis or controls (P , 0.01 for all), whereas lathosterol was correlated with the steatosis grade (r = 0.320, P , 0.050). Conclusions: Increased serum stigmasterol and avenasterol concentrations parallel the portal inflammation and cholestasis during PN, thereby reinforcing their contribution to IFALD. A bile acid malabsorption–driven increase in cholesterol synthesis underpins persistent liver steatosis after weaning off PN. Serum Cholestanol reflects liver injury in IF patients. Am J Clin Nutr 2014;100:1085–94.
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polymorphisms in the abcg5 and abcg8 genes associate with cholesterol absorption and insulin sensitivity
Journal of Lipid Research, 2004Co-Authors: Helena Gylling, Maarit Hallikainen, Jussi Pihlajamäki, Jyrki J. Ågren, Markku Laakso, Radhakrishnan A. Rajaratnam, Rainer Rauramaa, Tatu A MiettinenAbstract:The roles of polymorphisms of the sitosterolemia genes ABCG5 and ABCG8 in the regulation of cholesterol metabolism and insulin sensitivity were studied in mildly hypercholesterolemic noncoronary subjects (n = 263, 144 menand 119 women) divided into tertiles by baseline serum Cholestanol-to-cholesterol ratio (≤118.3 and ≥147.7 10 2 × mmol/mol cholesterol), a surrogate marker of cholesterol absorption efficiency. The lowest Cholestanol tertile was associated with high body mass index (BMI), plasma glucose, serum insulin and triglycerides, and cholesterol synthesis markers (cholestenol, desmosterol, lathosterol) and low HDL cholesterol and cholesterol absorption markers (campesterol, sitosterol) (P <0.01 for all). The 19H allele of the ABCG8 gene accumulated in the lowest Cholestanol tertile (P < 0.001) and was associated with low total and LDL cholesterol and absorption markers and with high synthesis markers (P < 0.05 for all). The 604E allele of the ABCG5 gene in men was associated with high BMI, plasma insulin, low serum sitosterol, and high serum cholestenol levels (P < 0.05 for all). In a subgroup of 71 men, the 604E allele was associated with insulin resistance measured with the hyperinsulinemic euglycemic clamp. In conclusion, low cholesterol absorption efficiency was associated with characteristics of the metabolic syndrome. Low serum cholesterol and cholesterol absorption were linked to the D19H polymorphism of the ABCG8 gene, and characteristics of the insulin resistance syndrome in men were linked with the Q604E polymorphism of the ABCG5 gene.
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Polymorphisms in the ABCG5 and ABCG8 genes associate with cholesterol absorption and insulin sensitivity
Journal of lipid research, 2004Co-Authors: Helena Gylling, Maarit Hallikainen, Jussi Pihlajamäki, Jyrki J. Ågren, Markku Laakso, Radhakrishnan A. Rajaratnam, Rainer Rauramaa, Tatu A MiettinenAbstract:The roles of polymorphisms of the sitosterolemia genes ABCG5 and ABCG8 in the regulation of cholesterol metabolism and insulin sensitivity were studied in mildly hypercholesterolemic noncoronary subjects (n = 263, 144 menand 119 women) divided into tertiles by baseline serum Cholestanol-to-cholesterol ratio (≤118.3 and ≥147.7 10 2 × mmol/mol cholesterol), a surrogate marker of cholesterol absorption efficiency. The lowest Cholestanol tertile was associated with high body mass index (BMI), plasma glucose, serum insulin and triglycerides, and cholesterol synthesis markers (cholestenol, desmosterol, lathosterol) and low HDL cholesterol and cholesterol absorption markers (campesterol, sitosterol) (P
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noncholesterol sterols and cholesterol lowering by long term simvastatin treatment in coronary patients relation to basal serum Cholestanol
Arteriosclerosis Thrombosis and Vascular Biology, 2000Co-Authors: Tatu A Miettinen, Timo E Strandberg, Helena GyllingAbstract:Abstract —Coronary patients with low baseline ratios of serum Cholestanol and plant sterols to cholesterol (indicating low cholesterol absorption) but not those with high ratios (high absorption) experienced reduced recurrences of coronary events during simvastatin treatment in the Scandinavian Simvastatin Survival Study. Thus, in the present study, serum cholesterol, its precursor sterols (reflecting cholesterol synthesis), plant sterols (campesterol and sitosterol), and Cholestanol were measured before and during a 5-year period of placebo treatment (n=433) and simvastatin treatment (n=434) in patients from a subgroup of the Scandinavian Simvastatin Survival Study to determine whether changes in cholesterol synthesis and serum levels were related to cholesterol absorption. Serum cholesterol level was unchanged, the ratios of cholesterol precursor sterols to cholesterol were decreased, and the ratios of plant sterols to cholesterol were increased in relation to increasing baseline ratios of Cholestanol quartiles. The latter predicted 5-year ratios and simvastatin-induced reductions of the precursor sterols, with the lowering of the ratios (cholesterol synthesis reduction) being almost twice higher in the lowest versus the highest quartile. The ratios of plant sterols, especially campesterol, to cholesterol were markedly increased during simvastatin treatment, mostly in subjects with the highest baseline Cholestanol quartiles. Simvastatin reduced serum cholesterol more ( P =0.003) in the lowest versus the highest Cholestanol quartile during the 5-year treatment period. The results show for the first time that baseline cholesterol metabolism, measured by serum noncholesterol sterols, predicts the effectiveness of simvastatin in reducing cholesterol synthesis and serum levels of cholesterol. The drug suppresses the synthesis of cholesterol markedly more effectively in subjects with high than with low baseline synthesis but reduces respective serum cholesterol levels less markedly than synthesis. Subjects with high cholesterol absorption and low synthesis may need a combination therapy to lower more effectively their serum cholesterol levels and prevent an increase in the levels of plant sterols.
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the metabolism of Cholestanol in primary biliary cirrhosis
Journal of Hepatology, 1996Co-Authors: Helena Gylling, Matti Vuoristo, Farkkila Martti, Miettinen A TatuAbstract:Abstract Background/Aims: The concentration of serum Cholestanol, a 5α-saturated derivative of cholesterol, is increased in primary biliary cirrhosis proportionally to impaired liver function for unknown reasons. The purpose of this study was to analyze serum Cholestanol level and its biliary and fecal elimination, and relate the results to cholesterol absorption and metabolism. Methods: Sixteen patients with primary biliary cirrhosis and 44 non-primary biliary cirrhosis controls were studied. Squalene and non-cholesterol sterols were analyzed by gas-liquid chromatography, cholesterol absorption by the peroral double-isotope continuous feeding method, and neutral and acidic sterols in bile and feces by gas-liquid chromatography. Results: In primary biliary cirrhosis, the mean level of serum cholesterol was normal, but the Cholestanol/cholesterol proportion was increased 4-fold, and the proportion was related to the serum bile acid and bilirubin levels. The mean biliary Cholestanol proportion and the biliary secretion rate were increased 5- and 2-fold, respectively, suggesting that at low Cholestanol absorption Cholestanol synthesis was increased. Calculated clearance of serum Cholestanol into bile was decreased. The fecal output was within the control limits, so that intestinal Cholestanol production was lowered in primary biliary cirrhosis. In addition, serum and biliary plant sterol proportions were increased in primary biliary cirrhosis, but their biliary secretion was unchanged, while those of cholesterol, bile acids, phospholipids, and cholesterol precursor sterols were markedly reduced. Conclusions: We conclude that an enhanced Cholestanol synthesis and a cholestasis-induced decrease in biliary clearance of serum Cholestanol contribute to the excessively high serum Cholestanol level in primary biliary cirrhosis. In addition, reduced bile acid synthesis may contribute to the increased serum Cholestanol content.
Juhani Tuominen - One of the best experts on this subject based on the ideXlab platform.
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other clinical studyserum Cholestanol cholesterol precursors and plant sterols during placebo controlled treatment of primary biliary cirrhosis with ursodeoxycholic acid or colchicine
Hepatology, 1995Co-Authors: Tatu A Miettinen, Martti Farkkila, Matti Vuoristo, Annaliisa Karvonen, Rauli Leino, J Lehtola, Claes Friman, K Seppala, Juhani TuominenAbstract:A randomized placebo-controlled 2-year study was performed in 69 patients with primary biliary cirrhosis (PBC) on serum lipids during ursodeoxycholic acid (URSO) and colchicine treatments. In addition to serum bilirubin and alkaline phosphatase (AFOS), two variables considered to reflect liver function, serum lipoproteins, cholesterol precursors (squalene, Γ8-cholestenol, lathosterol and desmosterol), markers of cholesterol synthesis, Cholestanol and plant sterols (campesterol and sitosterol), markers of liver function and cholesterol absorption, were studied before and during the treatments. Serum bilirubin was inconsistently improved by URSO, whereas improvement of AFOS values was better by URSO than colchicine, especially in patients with initially more advanced PBC. Serum total cholesterol was reduced by both drugs, very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) cholesterol by URSO. Cholesterol precursor sterols were increased by both URSO and colchicine mainly in patients with initially less severe PBC. On the other hand, the Cholestanol values were markedly increased initially, and the values were related to bilirubin during the 2-year period, were further increased in the placebo group, and reduced in the URSO and colchicine groups, so that the improvement was highest in the URSO-treated patients with the severe form of PBC. The increase of the serum plant sterols, particularly that of sitosterol, was retarded by the two drugs so that the campesterol/sitosterol ratio, which was related to serum bilirubin, was increased especially in the cases with initially more advanced PBC. The present findings show that the serum Cholestanol level and the campesterol/sitosterol ratio, two variables characterizing end-stage PBC, are modestly but significantly improved by long-term URSO or colchicine treatment, but virtually none of the excessively increased Cholestanol values are normalized.
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serum Cholestanol cholesterol precursors and plant sterols during placebo controlled treatment of primary biliary cirrhosis with ursodeoxycholic acid or colchicine
Hepatology, 1995Co-Authors: Tatu A Miettinen, Martti Farkkila, Matti Vuoristo, Annaliisa Karvonen, Rauli Leino, J Lehtola, Claes Friman, K Seppala, Juhani TuominenAbstract:A randomized placebo-controlled 2-year study was performed in 69 patients with primary biliary cirrhosis (PBC) on serum lipids during ursodeoxycholic acid (URSO) and colchicine treatments. In addition to serum bilirubin and alkaline phosphatase (AFOS), two variables considered to reflect liver function, serum lipoproteins, cholesterol precursors (squalene, delta 8-cholestenol, lathosterol and desmosterol), markers of cholesterol synthesis, Cholestanol and plant sterols (campesterol and sitosterol), markers of liver function and cholesterol absorption, were studied before and during the treatments. Serum bilirubin was inconsistently improved by URSO, whereas improvement of AFOS values was better by URSO than colchicine, especially in patients with initially more advanced PBC. Serum total cholesterol was reduced by both drugs, very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) cholesterol by URSO. Cholesterol precursor sterols were increased by both URSO and colchicine mainly in patients with initially less severe PBC. On the other hand, the Cholestanol values were markedly increased initially, and the values were related to bilirubin during the 2-year period, were further increased in the placebo group, and reduced in the URSO and colchicine groups, so that the improvement was highest in the URSO-treated patients with the severe form of PBC. The increase of the serum plant sterols, particularly that of sitosterol, was retarded by the two drugs so that the campesterol/sitosterol ratio, which was related to serum bilirubin, was increased especially in the cases with initially more advanced PBC.(ABSTRACT TRUNCATED AT 250 WORDS)
Irina A Pikuleva - One of the best experts on this subject based on the ideXlab platform.
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Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum
Journal of Biological Chemistry, 2017Co-Authors: Natalia Mast, Ingemar Bjorkhem, Kyle W. Anderson, Illarion V Turko, Curtis Tatsuoka, Yong Li, Irina A PikulevaAbstract:Abstract Cytochrome P450 27A1 (CYP27A1 or sterol 27-hydroxylase) is a ubiquitous, multifunctional enzyme catalyzing regio- and stereo-specific hydroxylation of different sterols. In humans, complete CYP27A1 deficiency leads to cerebrotendinous xanthomatosis or nodule formation in tendons and brain (preferentially in the cerebellum) rich in cholesterol and Cholestanol, the 5α-saturated analog of cholesterol. In Cyp27a1-/- mice, xanthomas are not formed, despite a significant Cholestanol increase in the brain and cerebellum. The mechanism behind Cholestanol production has been clarified, yet little is known about its metabolism, except that CYP27A1 might metabolize Cholestanol. It also is unclear why CYP27A1 deficiency results in preferential Cholestanol accumulation in the cerebellum. We hypothesized that Cholestanol might be metabolized by CYP46A1, the principal cholesterol 24-hydroxylase in the brain. We quantified sterols along with CYP27A1 and CYP46A1 in mouse models (Cyp27a1-/-, Cyp46a1-/-, Cyp27a1-/- Cyp46a1-/-, and two wild type strains) and human brain specimens. In vitro experiments with purified P450s were conducted as well. We demonstrate that CYP46A1 is involved in Cholestanol removal from the brain, and that several factors contribute to the preferential increase in Cholestanol in the cerebellum arising from CYP27A1 deficiency. These factors include: (i) low cerebellar abundance of CYP46A1 and high cerebellar abundance of CYP27A1, whose lack likely selectively increases the cerebellar Cholestanol production; (ii) spatial separation in the cerebellum of cholesterol/Cholestanol-metabolizing P450s from a pool of metabolically available Cholestanol; and (iii) weak cerebellar regulation of cholesterol biosynthesis. We identified a new physiological role of CYP46A1, an important brain enzyme and cytochrome P450 that could be activated pharmacologically.
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mechanism of accumulation of cholesterol and Cholestanol in tendons and the role of sterol 27 hydroxylase cyp27a1
Arteriosclerosis Thrombosis and Vascular Biology, 2002Co-Authors: Sara Von Bahr, Irina A Pikuleva, Tomas Movin, Nikos Papadogiannakis, Per Ronnow, Ulf Diczfalusy, Ingemar BjorkhemAbstract:Objective — Tendon xanthomas are deposits of lipids and connective tissue commonly found in hypercholesterolemic patients. Macrophages are likely to be responsible for the lipid accumulation. Normolipidemic patients with the rare disease cerebrotendinous xanthomatosis, lacking the enzyme sterol 27-hydroxylase (CYP27A1), develop prominent xanthomas in tendons and brain containing both Cholestanol and cholesterol, with a Cholestanol:cholesterol ratio higher than that in the circulation. Because of its ability to convert cholesterol into polar metabolites that leave the cells faster, CYP27A1 has been suggested to be an antiatherogenic enzyme. The hypothesis was tested that tendons contain CYP27A1 that may be of importance for the normal efflux of both steroids. Methods and Results — Western blotting and combined gas chromatography-mass spectrometry showed that human tendons contain significant amounts of CYP27A1 and its product, 27-hydroxycholesterol. Immunohistochemistry showed that CYP27A1 is present in macrophages and tenocytes. The tendons also contained Cholestanol, with a Cholestanol:cholesterol ratio slightly higher than that in the circulation. Recombinant human CYP27A1, and cultured human macrophages containing this enzyme, had similar activity toward cholesterol and Cholestanol. After loading of macrophages with labeled cholesterol and Cholestanol, there was an efflux of these steroids in both unmetabolized and 27-oxygenated form, resulting in a significant cellular accumulation of Cholestanol compared with cholesterol. Conclusion — The results are consistent with the possibility that CYP27A1 is of importance for the efflux of both cholesterol and Cholestanol from tendons.