Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice.
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/1) for a point mutation in the ferrochelatase gene and in wild-type controls (1/1). 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/1 and 1/1 livers. Plasma cholesterol in fch/fch mice (9.9 +/- 6.4 mM) is elevated when compared with fch/1 and 1/1 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 1/1, fch/1, 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.
Bloks
V W
VW
Departments of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, University Hospital Groningen, 9700 RB Groningen, The Netherlands.
Plösch
T
T
van Goor
H
H
Roelofsen
H
H
Baller
J
J
Havinga
R
R
Verkade
H J
HJ
van Tol
A
A
Jansen
P L
PL
Kuipers
F
F
D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D005294:Ferrochelatase / Q000235:genetics / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis / Q000097:blood; D008073:Lipoprotein-X / Q000097:blood / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D046351:Protoporphyria, Erythropoietic
D008055:Lipids; D008073:Lipoprotein-X; D008075:Lipoproteins, HDL; D005294:Ferrochelatase