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Robert D. Steiner - One of the best experts on this subject based on the ideXlab platform.
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Sterol Metabolism disorders and neurodevelopment-an update.
Developmental disabilities research reviews, 2013Co-Authors: Shibani Kanungo, Neelkamal Soares, Robert D. SteinerAbstract:CholeSterol has numerous quintessential functions in normal cell physiology, as well as in embryonic and postnatal development. It is a major component of cell membranes and myelin, and is a precursor of steroid hormones and bile acids. The development of the blood brain barrier likely around 12-18 weeks of human gestation makes the developing embryonic/fetal brain dependent on endogenous choleSterol synthesis. Known enzyme defects along the choleSterol biosynthetic pathway result in a host of neurodevelopmental and behavioral findings along with CNS structural anomalies. In this article, we review Sterol synthesis disorders in the pre- and post-squalene pathway highlighting neurodevelopmental aspects that underlie the clinical presentations and course of Smith-Lemli-Opitz Syndrome (SLOS), mevalonic aciduria (MVA) or the milder version hyper-immunoglobulinemia D and periodic fever syndrome (HIDS), Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1), congenital hemidysplasia with icthyosiform nevus and limb defects (CHILD) syndrome, CK syndrome, Sterol C4 methyl oxidase (SC4MOL) deficiency, X-linked dominant chondrodysplasia punctata 2(CDPX2)/ Conradi Hunermann syndrome, lathoSterolosis and desmoSterolosis, We also discuss current controversies and share thoughts on future directions in the field.
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treatment of smith lemli opitz syndrome and other Sterol disorders
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2012Co-Authors: Melissa D Svoboda, Yasemen Eroglu, Jill M Christie, Kurt A Freeman, Robert D. SteinerAbstract:Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive genetic condition with a broad phenotype that results from deficiency of the final enzyme of the choleSterol synthesis pathway. This defect causes low or low-normal plasma choleSterol levels and increased 7- and 8-dehydrocholeSterol (DHC) levels. Many therapies for SLOS and other disorders of Sterol Metabolism have been proposed, and a few of them have been undertaken in selected patients, but robust prospective clinical trials with validated outcome measures are lacking. We review the current literature and expert opinion on treatments for SLOS and other selected Sterol disorders, including dietary choleSterol therapy, statin treatment, bile acid supplementation, medical therapies, and surgical interventions, as well as directions for future therapies and treatment research.
Fabian F Moebius - One of the best experts on this subject based on the ideXlab platform.
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discovery of high affinity ligands of σ1 receptor erg2 and emopamil binding protein by pharmacophore modeling and virtual screening
Journal of Medicinal Chemistry, 2005Co-Authors: Christian Laggner, Hartmut Glossmann, Claudia Schieferer, Birgit Fiechtner, Gloria Poles, Remy D Hoffmann, Thierry Langer, Fabian F MoebiusAbstract:ERG2, emopamil binding protein (EBP), and sigma-1 receptor (σ1) are enzymes of Sterol Metabolism and an enzyme-related protein, respectively, that share high affinity for various structurally diverse compounds. To discover novel high-affinity ligands, pharmacophore models were built with Catalyst based upon a series of 23 structurally diverse chemicals exhibiting Ki values from 10 pM to 100 μM for all three proteins. In virtual screening experiments, we retrieved drugs that were previously reported to bind to one or several of these proteins and also tested 11 new hits experimentally, of which three, among them raloxifene, had affinities for σ1 or EBP of <60 nM. When used to search a database of 3525 biochemicals of intermediary Metabolism, a slightly modified ERG2 pharmacophore model successfully retrieved 10 substrate candidates among the top 28 hits. Our results indicate that inhibitor-based pharmacophore models for σ1, ERG2, and EBP can be used to screen drug and metabolite databases for chemically di...
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mutations in the delta7 Sterol reductase gene in patients with the smith lemli opitz syndrome
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Barbara U Fitzky, Martina Witschbaumgartner, Martin Erdel, Joon No Lee, Young Ki Paik, Hartmut Glossmann, Gerd Utermann, Fabian F MoebiusAbstract:The Smith–Lemli–Opitz syndrome (SLOS) is an inborn disorder of Sterol Metabolism with characteristic congenital malformations and dysmorphias. All patients suffer from mental retardation. Here we identify the SLOS gene as a Δ7-Sterol reductase (DHCR7, EC 1.3.1.21) required for the de novo biosynthesis of choleSterol. The human and murine genes were characterized and assigned to syntenic regions on chromosomes 11q13 and 7F5 by fluorescense in situ hybridization. Among the mutations found in patients with the SLOS, are missense (P51S, T93M, L99P, L157P, A247V, V326L, R352W, C380S, R404C, and G410S), nonsense (W151X), and splice site (IVS8–1G>C) mutations as well as an out of frame deletion (720–735 del). The missense mutations L99P, V326L, R352W, R404C, and G410S reduced heterologous protein expression by >90%. Our results strongly suggest that defects in the DHCR7 gene cause the SLOS.
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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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, Illarion V Turko, Curtis Tatsuoka, Kyle Anderson, Joseph Lin, Irina A PikulevaAbstract:Cytochrome P450 27A1 (CYP27A1 or Sterol 27-hydroxylase) is a ubiquitous, multifunctional enzyme catalyzing regio- and stereospecific 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, the lack of which probably 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.
Richard I. Kelley - One of the best experts on this subject based on the ideXlab platform.
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abnormal Sterol Metabolism in holoprosencephaly studies in cultured lymphoblasts
Journal of Medical Genetics, 2007Co-Authors: Dorothea Haas, Richard I. Kelley, Janine Morgenthaler, Felicitas Lacbawan, Bob Long, Heiko Runz, Sven F Garbade, Johannes Zschocke, Juergen G Okun, Georg F HoffmannAbstract:Objective: Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans. The etiology is heterogeneous and remains unexplained in approximately 75% of patients. Because perturbations of choleSterol homeostasis are an important model system to study HPE pathogenesis in animals, we examined choleSterol biosynthesis in lymphoblastoid cell lines of 228 HPE patients. Methods: Using [2-14C]acetate as substrate, we developed an in vitro loading test that clearly identifies abnormal elevations of C27 Sterols in lymphoblast-derived cells. Results: Twenty-two HPE cell lines (9.6%) had abnormal Sterol pattern in the in vitro loading test. In one previously reported patient, Smith-Lemli-Opitz syndrome (SLOS) was diagnosed, whereas others also had clearly reduced choleSterol biosynthesis of uncertain cause. The mean (SD) choleSterol level was 58 (15.4)% and 82 (4.7)% of total Sterols in these cell lines and controls, respectively. The pattern of accumulating Sterols was different from known defects of choleSterol biosynthesis. In 6 of the patients with abnormal lymphoblast choleSterol Metabolism, additional mutations in genes known to be associated with HPE or chromosomal abnormalities were observed. Conclusions: Impaired choleSterol biosynthesis may be a contributing factor in the cause of HPE and should be considered in the evaluation of causes of HPE, even if mutations in HPE-associated genes have already been found.
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Abnormal Sterol Metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia
American Journal of Medical Genetics, 2002Co-Authors: Richard I. Kelley, Lisa E. Kratz, Rivka L. Glaser, Michael L. Netzloff, Linda Miller Wolf, Ethylin Wang JabsAbstract:Antley-Bixler syndrome (ABS) is a rare multiple anomaly syndrome comprising radiohumeral synostosis, bowed femora, fractures of the long bones, premature fusion of the calvarial sutures, severe midface hypoplasia, proptosis, choanal atresia, and, in some, ambiguous genitalia. Of fewer than 40 patients described to date, most have been sporadic, although reports of parental consanguinity and affected sibs of both sexes suggests autosomal recessive inheritance in some families. Known genetic causes among sporadic cases of ABS or ABS-like syndromes are missense mutations in the IgII and IgIII regions of FGFR2, although the assignment of the diagnosis of ABS to such children has been disputed. A third cause of an ABS-like phenotype is early in utero exposure to fluconazole, an inhibitor of lanoSterol 14-alpha-demethylase. The fourth proposed cause of ABS is digenic inheritance combining heterozygosity or homozygosity for steroid 21-hydroxylase deficiency with effects from a second gene at an unknown locus. Because fluconazole is a strong inhibitor of lanoSterol 14-alpha-demethylase (CYP51), we evaluated Sterol Metabolism in lymphoblast cell lines from an ABS patient without a known FGFR2 mutation and from a patient with an FGFR2 mutation and ABS-like manifestations. When grown in the absence of choleSterol to stimulate choleSterol biosynthesis, the cells from the ABS patient with ambiguous genitalia but without an FGFR2 mutation accumulated markedly increased levels of lanoSterol and dihydrolanoSterol. Although the abnormal Sterol profile suggested a deficiency of lanoSterol 14-alpha-demethylase, mutational analysis of its gene, CYP51, disclosed no obvious pathogenic mutation in any of its 10 exons or exon-intron boundaries. Sterol Metabolism in lymphoblasts from the phenotypically unaffected mother was normal. Our results suggest that ABS can occur in a patient with an intrinsic defect of choleSterol biosynthesis at the level of lanoSterol 14-alpha-demethylase, although the genetic nature of the deficiency remains to be determined. © 2002 Wiley-Liss, Inc.
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abnormal Sterol Metabolism in patients with conradi hunermann happle syndrome and sporadic lethal chondrodysplasia punctata
American Journal of Medical Genetics, 1999Co-Authors: Richard I. Kelley, William G Wilcox, M Smith, Lisa Kratz, Ann B Moser, David S RimoinAbstract:The term, "chondrodysplasia punctata" (CDP) denotes a pattern of abnormal punctate calcification of dystrophic epiphyseal cartilage and certain other cartilaginous structures, such as the larynx. CDP occurs in a variety of genetic disorders associated with skeletal dwarfism and can also be caused by prenatal exposure to warfarin. Although the most studied clinical syndrome with CDP, rhizomelic chondrodysplasia punctata (RCDP), is known to be caused by several different abnormalities of plasmalogen biosynthesis, there are many other genetic disorders with CDP for which the biochemical cause is unknown. Because patients with Smith-Lemli-Opitz syndrome, a primary disorder of Sterol biosynthesis, often have rhizomesomelic limb shortness and, less commonly, CDP, we assessed Sterol levels and Metabolism in patients with different clinical forms of CDP. By quantitative Sterol analysis of a variety of tissues, we identified 5 patients with similar radiological findings and abnormally increased levels of 8-dehydrocholeSterol and cholest-8(9)-en-3beta-ol, suggesting a deficiency of 3beta-hydroxysteroid-delta8,delta7-isomerase, a principal enzyme of choleSterol biosynthesis. Cultured cells available from one patient showed increased levels of the same two Sterols, decreased synthesis of choleSterol, and a pattern of inhibition by triparanol and AY-9944 consistent with a deficiency of 3beta-hydroxysteroid-delta8,delta7-isomerase. Clinical diagnoses among the 5 patients included X-linked dominant Conradi-Hunermann-Happle syndrome and nonspecific lethal CDP. We conclude that abnormal choleSterol biosynthesis is a characteristic of some clinical syndromes with rhizomesomelic dwarfing and CDP.
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variant rsh smith lemli opitz syndrome with atypical Sterol Metabolism
American Journal of Medical Genetics, 1998Co-Authors: Arne J Anderson, Mark J Stephan, William O Walker, Richard I. KelleyAbstract:The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive malformation syndrome comprising microcephaly, developmental and growth retardation, characteristic facial anomalies, midline cleft palate, and genital and limb anomalies. Recently, biochemical evidence of an inborn error of choleSterol biosynthesis at the level of 7-dehydrocholeSterol (7DHC) reductase was reported in children and adults with RSH/SLOS. We report on two sibs with a variant form of RSH/SLOS whose Sterol Metabolism in cultured lymphoblasts is abnormal but differs from that of patients with classical RSH/SLOS. The children have relatively mild physical and developmental abnormalities, but a phenotype still consistent with the diagnosis of RSH/SLOS. Their plasma choleSterol levels are only mildly depressed, and they have less markedly increased plasma levels of 7DHC than most patients with classical RSH/SLOS. Cultured lymphoblasts from our patients accumulated 7DHC to the same degree as classical RSH/SLOS lymphoblast when grown with choleSterol-depleted fetal calf serum. However, unlike other RSH/SLOS cells, the increase in cellular 7DHC levels was not suppressed when the cells were grown in the presence of choleSterol from untreated fetal calf serum. The parents' Sterol Metabolism was also strikingly abnormal in that the levels of 7DHC in their lymphoblasts were markedly elevated compared with those of lymphoblasts from other RSH/SLOS parents. Our findings suggest that these mildly affected RSH/SLOS sibs may have a genetic disorder of Sterol Metabolism that is related to but biochemically different from classical RSH/SLOS, possibly one affecting intracellular transport of Sterols.
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holoprosencephaly in rsh smith lemli opitz syndrome does abnormal choleSterol Metabolism affect the function of sonic hedgehog
American Journal of Medical Genetics, 1996Co-Authors: Richard I. Kelley, Raoul C.m. Hennekam, Erich Roessler, Gerald L Feldman, Kenjiro Kosaki, Marilyn C Jones, Janice C Palumbos, Maximilian MuenkeAbstract:The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive malformation syndrome associated with increased levels of 7-dehydro-choleSterol (7-DHC) and a defect of choleSterol biosynthesis at the level of 3 beta-hydroxy-steroid-delta7-reductase (7-DHC reductase). Because rats exposed to inhibitors of 7-DHC reductase during development have a high frequency of holoprosencephaly (HPE) [Roux et al., 1979], we have undertaken a search for biochemical evidence of RSH/SLOS and other possible defects of Sterol Metabolism among patients with various forms of HPE. We describe 4 patients, one with semilobar HPE and three others with less complete forms of the HPE sequence, in whom we have made a biochemical diagnosis of RSH/SLOS. The clinical and biochemical spectrum of these and other patients with RSH/SLOS suggests a role of abnormal Sterol Metabolism in the pathogenesis of their malformations. The association of HPE and RSH/SLOS is discussed in light of the recent discoveries that mutations in the embryonic patterning gene, Sonic Hedgehog (SHH), can cause HPE in humans and that the sonic hedgehog protein product undergoes autoproteolysis to form a choleSterol-modified active product. These clinical, biochemical, and molecular studies suggest that HPE and other malformations in SLOS may be caused by incomplete or abnormal modification of the sonic hedgehog protein and, possible, other patterning proteins of the hedgehog class, a hypothesis testable in somatic cell systems.
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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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, Illarion V Turko, Curtis Tatsuoka, Kyle Anderson, Joseph Lin, Irina A PikulevaAbstract:Cytochrome P450 27A1 (CYP27A1 or Sterol 27-hydroxylase) is a ubiquitous, multifunctional enzyme catalyzing regio- and stereospecific 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, the lack of which probably 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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dietary choleSterol supplementation to a plant based diet suppresses the complete pathway of choleSterol synthesis and induces bile acid production in atlantic salmon salmo salar l
British Journal of Nutrition, 2014Co-Authors: Trond M Kortner, Ingemar Bjorkhem, Aleksei Krasnov, Gerrit Timmerhaus, Ashild KrogdahlAbstract:Plants now supply more than 50 % of protein in Norwegian salmon aquafeeds. The inclusion of plant protein in aquafeeds may be associated with decreased lipid digestibility and choleSterol and bile salt levels, indicating that the replacement of fishmeal with plant protein could result in inadequate supplies of choleSterol in fish. A reduction in feed efficiency, fish growth and pathogen resistance is often observed in parallel to alterations in Sterol Metabolism. Previous studies have indicated that the negative effects induced by plant components can be attenuated when diets are supplemented with choleSterol. The present study evaluated the effects of dietary choleSterol supplementation (1·5 %) in Atlantic salmon fed a plant-based diet for 77 d. The weights of body, intestines and liver were recorded and blood, tissues, faeces, chyme and bile were sampled for the evaluation of effects on growth, nutrient utilisation and Metabolism, and transcriptome and metabolite levels, with particular emphasis on Sterol Metabolism and organ structure and function. CholeSterol supplementation did not affect the growth or organ weights of Atlantic salmon, but seemed to promote the induction of choleSterol and plant Sterol efflux in the intestine while suppressing Sterol uptake. CholeSterol biosynthesis decreased correspondingly and conversion into bile acids increased. The marked effect of choleSterol supplementation on bile acid synthesis suggests that dietary choleSterol can be used to increase bile acid synthesis in fish. The present study clearly demonstrated how Atlantic salmon adjusted their metabolic functions in response to the dietary load of choleSterol. It has also expanded our understanding of Sterol Metabolism and turnover, adding to the existing, rather sparse, knowledge of these processes in fish.