Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice1
Erythropoietic protoporphyria (EPP) is an inherited disorder of heme synthesis caused by deficiency of the mitochondrial enzyme ferrochelatase. EPP in humans is associated with liver disease, hypertriglyceridemia, and a low level of high density lipoprotein (HDL) cholesterol. To explore consequences...
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Elsevier
2001-01-01
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Series: | Journal of Lipid Research |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520323348 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Vincent W. Bloks Torsten Plösch Harry van Goor Han Roelofsen Juul Baller Rick Havinga Henkjan J. Verkade Aad van Tol Peter L.M. Jansen Folkert Kuipers |
spellingShingle |
Vincent W. Bloks Torsten Plösch Harry van Goor Han Roelofsen Juul Baller Rick Havinga Henkjan J. Verkade Aad van Tol Peter L.M. Jansen Folkert Kuipers Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice1 Journal of Lipid Research lipoprotein-X very low density lipoprotein high density lipoprotein cholesterol bile mdr2 P-glycoprotein |
author_facet |
Vincent W. Bloks Torsten Plösch Harry van Goor Han Roelofsen Juul Baller Rick Havinga Henkjan J. Verkade Aad van Tol Peter L.M. Jansen Folkert Kuipers |
author_sort |
Vincent W. Bloks |
title |
Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice1 |
title_short |
Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice1 |
title_full |
Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice1 |
title_fullStr |
Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice1 |
title_full_unstemmed |
Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice1 |
title_sort |
hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice1 |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2001-01-01 |
description |
Erythropoietic protoporphyria (EPP) is an inherited disorder of heme synthesis caused by deficiency of the mitochondrial enzyme ferrochelatase. EPP in humans is associated with liver disease, hypertriglyceridemia, and a low level of high density lipoprotein (HDL) cholesterol. To explore consequences of ferrochelatase deficiency in lipid metabolism, we have analyzed hepatic lipid content and plasma lipoprotein levels in chow-fed BALB/c mice homozygous (fch/fch) or heterozygous (fch/+) for a point mutation in the ferrochelatase gene and in wild-type controls (+/+). Livers of fch/fch mice show bile duct proliferation and biliary fibrosis, but bile formation is not impaired. The free cholesterol content of fch/fch livers is significantly increased when compared with fch/+ and +/+ livers. Plasma cholesterol in fch/fch mice (9.9 ± 6.4 mM) is elevated when compared with fch/+ and +/+ mice (2.9 ± 0.2 and 2.5 ± 0.3 mM, respectively), because of an increased cholesterol content in the very low density lipoprotein-sized fractions, whereas HDL cholesterol is reduced. The ratio of cholesteryl ester to free cholesterol is 4.3 ± 0.6, 3.3 ± 0.3, and 0.3 ± 0.1 in the plasma of +/+, fch/+, and fch/fch mice, respectively. The latter is not due to reduced lecithin:cholesterol acyltransferase activity in plasma of fch/fch mice but to the presence of lipoprotein-X (Lp-X), a particle composed of bile-type lipids usually seen only in cholestatic conditions. Expression of mdr2, essential for biliary phospholipid/ cholesterol secretion, is increased in fch/fch livers. In spite of this, biliary phospholipid/cholesterol secretion is reduced relative to that of bile salts. It is postulated that an inability of bile salts to stimulate lipid secretion adequately leads to formation of Lp-X in this noncholestatic condition. Distinct atherosclerotic lesions were found in aged fch/fch mice. Thus, ferrochelatase deficiency in mice leads to liver disease associated with altered hepatic lipid metabolism, a characteristic hyperlipidemia, and development of atherosclerosis.—Bloks, V. W., T. Plösch, H. van Goor, H. Roelofsen, J. Baller, R. Havinga, H. J. Verkade, A. van Tol, P. L. M. Jansen, and F. Kuipers. Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice. J. Lipid Res. 2001. 42: 41–50. |
topic |
lipoprotein-X very low density lipoprotein high density lipoprotein cholesterol bile mdr2 P-glycoprotein |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520323348 |
work_keys_str_mv |
AT vincentwbloks hyperlipidemiaandatherosclerosisassociatedwithliverdiseaseinferrochelatasedeficientmice1 AT torstenplosch hyperlipidemiaandatherosclerosisassociatedwithliverdiseaseinferrochelatasedeficientmice1 AT harryvangoor hyperlipidemiaandatherosclerosisassociatedwithliverdiseaseinferrochelatasedeficientmice1 AT hanroelofsen hyperlipidemiaandatherosclerosisassociatedwithliverdiseaseinferrochelatasedeficientmice1 AT juulballer hyperlipidemiaandatherosclerosisassociatedwithliverdiseaseinferrochelatasedeficientmice1 AT rickhavinga hyperlipidemiaandatherosclerosisassociatedwithliverdiseaseinferrochelatasedeficientmice1 AT henkjanjverkade hyperlipidemiaandatherosclerosisassociatedwithliverdiseaseinferrochelatasedeficientmice1 AT aadvantol hyperlipidemiaandatherosclerosisassociatedwithliverdiseaseinferrochelatasedeficientmice1 AT peterlmjansen hyperlipidemiaandatherosclerosisassociatedwithliverdiseaseinferrochelatasedeficientmice1 AT folkertkuipers hyperlipidemiaandatherosclerosisassociatedwithliverdiseaseinferrochelatasedeficientmice1 |
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doaj-c40b38ff1c964478b3e645464caa251b2021-04-27T04:42:21ZengElsevierJournal of Lipid Research0022-22752001-01-014214150Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice1Vincent W. Bloks0Torsten Plösch1Harry van Goor2Han Roelofsen3Juul Baller4Rick Havinga5Henkjan J. Verkade6Aad van Tol7Peter L.M. Jansen8Folkert Kuipers9Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, University Hospital Groningen, 9700 RB Groningen, The NetherlandsDepartment of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, University Hospital Groningen, 9700 RB Groningen, The NetherlandsDepartment of Pathology, Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, University Hospital Groningen, 9700 RB Groningen, The NetherlandsDepartment of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, University Hospital Groningen, 9700 RB Groningen, The NetherlandsDepartment of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, University Hospital Groningen, 9700 RB Groningen, The NetherlandsDepartment of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, University Hospital Groningen, 9700 RB Groningen, The NetherlandsDepartment of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, University Hospital Groningen, 9700 RB Groningen, The NetherlandsDepartment of Biochemistry, Erasmus University, 3000 RD Rotterdam, The NetherlandsDepartment of Gastroenterology, Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, University Hospital Groningen, 9700 RB Groningen, The NetherlandsTo whom correspondence should be addressed; Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, University Hospital Groningen, 9700 RB Groningen, The NetherlandsErythropoietic protoporphyria (EPP) is an inherited disorder of heme synthesis caused by deficiency of the mitochondrial enzyme ferrochelatase. EPP in humans is associated with liver disease, hypertriglyceridemia, and a low level of high density lipoprotein (HDL) cholesterol. To explore consequences of ferrochelatase deficiency in lipid metabolism, we have analyzed hepatic lipid content and plasma lipoprotein levels in chow-fed BALB/c mice homozygous (fch/fch) or heterozygous (fch/+) for a point mutation in the ferrochelatase gene and in wild-type controls (+/+). Livers of fch/fch mice show bile duct proliferation and biliary fibrosis, but bile formation is not impaired. The free cholesterol content of fch/fch livers is significantly increased when compared with fch/+ and +/+ livers. Plasma cholesterol in fch/fch mice (9.9 ± 6.4 mM) is elevated when compared with fch/+ and +/+ mice (2.9 ± 0.2 and 2.5 ± 0.3 mM, respectively), because of an increased cholesterol content in the very low density lipoprotein-sized fractions, whereas HDL cholesterol is reduced. The ratio of cholesteryl ester to free cholesterol is 4.3 ± 0.6, 3.3 ± 0.3, and 0.3 ± 0.1 in the plasma of +/+, fch/+, and fch/fch mice, respectively. The latter is not due to reduced lecithin:cholesterol acyltransferase activity in plasma of fch/fch mice but to the presence of lipoprotein-X (Lp-X), a particle composed of bile-type lipids usually seen only in cholestatic conditions. Expression of mdr2, essential for biliary phospholipid/ cholesterol secretion, is increased in fch/fch livers. In spite of this, biliary phospholipid/cholesterol secretion is reduced relative to that of bile salts. It is postulated that an inability of bile salts to stimulate lipid secretion adequately leads to formation of Lp-X in this noncholestatic condition. Distinct atherosclerotic lesions were found in aged fch/fch mice. Thus, ferrochelatase deficiency in mice leads to liver disease associated with altered hepatic lipid metabolism, a characteristic hyperlipidemia, and development of atherosclerosis.—Bloks, V. W., T. Plösch, H. van Goor, H. Roelofsen, J. Baller, R. Havinga, H. J. Verkade, A. van Tol, P. L. M. Jansen, and F. Kuipers. Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice. J. Lipid Res. 2001. 42: 41–50.http://www.sciencedirect.com/science/article/pii/S0022227520323348lipoprotein-Xvery low density lipoproteinhigh density lipoproteincholesterolbilemdr2 P-glycoprotein |