Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion
Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder characterized by low plasma cholesterol and high 7-dehydrocholesterol (7-DHC). Synthesis of cholesterol and 7-DHC and its metabolites is regulated by HMG-CoA reductase, whose activity can be measured by 24-h excretion of its product mevalonate....
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| Format: | Article |
| Language: | English |
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Elsevier
2002-10-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520327851 |
| _version_ | 1818646870354821120 |
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| author | Anuradha S. Pappu Robert D. Steiner Sonja L. Connor Donna P. Flavell Don S. Lin Lauren Hatcher D.Roger Illingworth William E. Connor |
| author_facet | Anuradha S. Pappu Robert D. Steiner Sonja L. Connor Donna P. Flavell Don S. Lin Lauren Hatcher D.Roger Illingworth William E. Connor |
| author_sort | Anuradha S. Pappu |
| collection | DOAJ |
| description | Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder characterized by low plasma cholesterol and high 7-dehydrocholesterol (7-DHC). Synthesis of cholesterol and 7-DHC and its metabolites is regulated by HMG-CoA reductase, whose activity can be measured by 24-h excretion of its product mevalonate. We devised a simple, non-invasive method for collecting 24-h urine in our subjects. With a background of a very low cholesterol diet, mean mevalonate excretion did not differ between controls and SLOS children, indicating that SLOS subjects have normal HMG-CoA reductase activity. In a short term feeding study, the effects of a high cholesterol diet in SLOS subjects include a significant 55% increase in plasma cholesterol levels and 39% decrease in mevalonate excretion and no change in plasma 7-DHC levels. However, in four SLOS subjects, fed a high cholesterol diet for 2–3 years, plasma cholesterol levels continued to increase, urinary mevalonate excretion remained low and total 7-DHC decreased significantly, likely from decreased total sterol synthesis.Thus, in SLOS subjects, HMG-CoA reductase activity was normal and was subject to normal cholesterol induced feedback inhibition. However, total sterol synthesis in SLOS may still be decreased because of increased diversion of mevalonate into the shunt pathway away from sterol synthesis. |
| first_indexed | 2024-12-17T00:53:30Z |
| format | Article |
| id | doaj.art-c0205209cf054c0780f20c98970d745e |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T00:53:30Z |
| publishDate | 2002-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-c0205209cf054c0780f20c98970d745e2022-12-21T22:09:42ZengElsevierJournal of Lipid Research0022-22752002-10-01431016611669Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretionAnuradha S. Pappu0Robert D. Steiner1Sonja L. Connor2Donna P. Flavell3Don S. Lin4Lauren Hatcher5D.Roger Illingworth6William E. Connor7Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, Oregon 97201; Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon 97201Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, Oregon 97201; Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon 97201Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, Oregon 97201; Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon 97201Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, Oregon 97201; Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon 97201Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, Oregon 97201; Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon 97201Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, Oregon 97201; Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon 97201Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, Oregon 97201; Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon 97201Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, Oregon 97201; Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon 97201Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder characterized by low plasma cholesterol and high 7-dehydrocholesterol (7-DHC). Synthesis of cholesterol and 7-DHC and its metabolites is regulated by HMG-CoA reductase, whose activity can be measured by 24-h excretion of its product mevalonate. We devised a simple, non-invasive method for collecting 24-h urine in our subjects. With a background of a very low cholesterol diet, mean mevalonate excretion did not differ between controls and SLOS children, indicating that SLOS subjects have normal HMG-CoA reductase activity. In a short term feeding study, the effects of a high cholesterol diet in SLOS subjects include a significant 55% increase in plasma cholesterol levels and 39% decrease in mevalonate excretion and no change in plasma 7-DHC levels. However, in four SLOS subjects, fed a high cholesterol diet for 2–3 years, plasma cholesterol levels continued to increase, urinary mevalonate excretion remained low and total 7-DHC decreased significantly, likely from decreased total sterol synthesis.Thus, in SLOS subjects, HMG-CoA reductase activity was normal and was subject to normal cholesterol induced feedback inhibition. However, total sterol synthesis in SLOS may still be decreased because of increased diversion of mevalonate into the shunt pathway away from sterol synthesis.http://www.sciencedirect.com/science/article/pii/S00222275203278517-dehydrocholesterol8-dehydrocholesterol3-hydroxy-3-methylglutaryl-coenzyme A reductase24-h urinesterolsmevalonate shunt pathway |
| spellingShingle | Anuradha S. Pappu Robert D. Steiner Sonja L. Connor Donna P. Flavell Don S. Lin Lauren Hatcher D.Roger Illingworth William E. Connor Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion Journal of Lipid Research 7-dehydrocholesterol 8-dehydrocholesterol 3-hydroxy-3-methylglutaryl-coenzyme A reductase 24-h urine sterols mevalonate shunt pathway |
| title | Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion |
| title_full | Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion |
| title_fullStr | Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion |
| title_full_unstemmed | Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion |
| title_short | Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion |
| title_sort | feedback inhibition of the cholesterol biosynthetic pathway in patients with smith lemli opitz syndrome as demonstrated by urinary mevalonate excretion |
| topic | 7-dehydrocholesterol 8-dehydrocholesterol 3-hydroxy-3-methylglutaryl-coenzyme A reductase 24-h urine sterols mevalonate shunt pathway |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520327851 |
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