Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice

VW Bloks, T Plosch, H van Goor, Johan Roelofsen, J Baller, R Havinga, HJ Verkade, A van Tol, PLM Jansen, F Kuipers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)581-591
Number of pages10
JournalJournal of Lipid Research
Issue number17
Publication statusPublished - Jan-2001
Event71st Scientific Session of the American-Heart-Association Meeting -
Duration: 8-Nov-199812-Nov-1998


  • lipoprotein-X
  • very low density lipoprotein
  • high density lipoprotein
  • cholesterol
  • bile
  • mdr2 P-glycoprotein
  • bile salt

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