出版社：American Society for Biochemistry and Molecular Biology
摘要：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.
关键词：lipoprotein-X ; very low density lipoprotein ; high density lipoprotein ; cholesterol ; bile ; mdr2 P-glycoprotein ; bile salt
