HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bloks, V. W. Articles by Kuipers, F. Search for Related Content PubMed PubMed Citation Articles by Bloks, V. W. Articles by Kuipers, F. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 42, 41-50, January 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

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

Correspondence to: Folkert Kuipers, at Groningen Institute for Drug Studies, CMC IV, Room Y2115, Academic Hospital Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands. Web page: www.LabPediatricsRug.nl, f.kuipers{at}med.rug.nl (E-mail)

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.

Supplementary key words: lipoprotein-X, very low density lipoprotein, high density lipoprotein, cholesterol, bile, mdr2 P-glycoprotein, bile salt

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. E. R. Gooijert, R. Havinga, A. R. Oosterloo-Duinkerken, E. E. A. Venekamp-Hoolsema, F. Kuipers, and H. J. Verkade Stimulation of fecal fat excretion and the disposal of protoporphyrin in a murine model for erythropoietic protoporphyria Am J Physiol Gastrointest Liver Physiol, August 1, 2007; 293(2): G510 - G516. [Abstract] [Full Text] [PDF]

				T. Gautier, U. J. F. Tietge, R. Boverhof, F. G. Perton, N. Le Guern, D. Masson, P. C. N. Rensen, L. M. Havekes, L. Lagrost, and F. Kuipers Hepatic lipid accumulation in apolipoprotein C-I-deficient mice is potentiated by cholesteryl ester transfer protein J. Lipid Res., January 1, 2007; 48(1): 30 - 40. [Abstract] [Full Text] [PDF]

				H. Atamna, J. Newberry, R. Erlitzki, C. S. Schultz, and B. N. Ames Biotin Deficiency Inhibits Heme Synthesis and Impairs Mitochondria in Human Lung Fibroblasts J. Nutr., January 1, 2007; 137(1): 25 - 30. [Abstract] [Full Text] [PDF]

				M. T. Flowers, A. K. Groen, A. T. Oler, M. P. Keller, Y. Choi, K. L. Schueler, O. C. Richards, H. Lan, M. Miyazaki, F. Kuipers, et al. Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet J. Lipid Res., December 1, 2006; 47(12): 2668 - 2680. [Abstract] [Full Text] [PDF]

				I. Duivenvoorden, P. J Voshol, P. C. Rensen, W. van Duyvenvoorde, J. A Romijn, J. J Emeis, L. M Havekes, and W. F Nieuwenhuizen Dietary sphingolipids lower plasma cholesterol and triacylglycerol and prevent liver steatosis in APOE*3Leiden mice. Am. J. Clinical Nutrition, August 1, 2006; 84(2): 312 - 321. [Abstract] [Full Text] [PDF]

				I. Duivenvoorden, B. Teusink, P. C. N. Rensen, F. Kuipers, J. A. Romijn, L. M. Havekes, and P. J. Voshol Acute inhibition of hepatic {beta}-oxidation in APOE*3Leiden mice does not affect hepatic VLDL secretion or insulin sensitivity J. Lipid Res., May 1, 2005; 46(5): 988 - 993. [Abstract] [Full Text] [PDF]

				R. Davies, A. Schuurman, C. R. Barker, B. Clothier, T. Chernova, F. M. Higginson, D. J. Judah, D. Dinsdale, R. E. Edwards, P. Greaves, et al. Hepatic Gene Expression in Protoporphyic Fech Mice Is Associated with Cholestatic Injury but Not a Marked Depletion of the Heme Regulatory Pool Am. J. Pathol., April 1, 2005; 166(4): 1041 - 1053. [Abstract] [Full Text] [PDF]

				X. Zhu, A. M. Herzenberg, M. Eskandarian, G. F. Maguire, J. W. Scholey, P. W. Connelly, and D. S. Ng A Novel in Vivo Lecithin-Cholesterol Acyltransferase (LCAT)-Deficient Mouse Expressing Predominantly LpX Is Associated with Spontaneous Glomerulopathy Am. J. Pathol., October 1, 2004; 165(4): 1269 - 1278. [Abstract] [Full Text] [PDF]

				M. Muurling, R. P. Mensink, H. Pijl, J. A. Romijn, L. M. Havekes, and P. J. Voshol A Fish Oil Diet Does Not Reverse Insulin Resistance despite Decreased Adipose Tissue TNF-{alpha} Protein Concentration in ApoE-3*Leiden Mice J. Nutr., November 1, 2003; 133(11): 3350 - 3355. [Abstract] [Full Text] [PDF]

				T. Plosch, T. Kok, V. W. Bloks, M. J. Smit, R. Havinga, G. Chimini, A. K. Groen, and F. Kuipers Increased Hepatobiliary and Fecal Cholesterol Excretion upon Activation of the Liver X Receptor Is Independent of ABCA1 J. Biol. Chem., September 6, 2002; 277(37): 33870 - 33877. [Abstract] [Full Text] [PDF]

				M. Guerre-Millo, C. Rouault, P. Poulain, J. Andre, V. Poitout, J. M. Peters, F. J. Gonzalez, J.-C. Fruchart, G. Reach, and B. Staels PPAR-{alpha}-Null Mice Are Protected From High-Fat Diet-Induced Insulin Resistance Diabetes, December 1, 2001; 50(12): 2809 - 2814. [Abstract] [Full Text] [PDF]

				A. R. Mensenkamp, B. Teusink, J. F.W. Baller, H. Wolters, R. Havinga, K. W. van Dijk, L. M. Havekes, and F. Kuipers Mice Expressing Only the Mutant APOE3Leiden Gene Show Impaired VLDL Secretion Arterioscler. Thromb. Vasc. Biol., August 1, 2001; 21(8): 1366 - 1372. [Abstract] [Full Text] [PDF]