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

Erythropoietic protoporphyria (EPP) is an inherited disorder of heme synthe sis caused by deficiency of the mitochondrial enzyme ferrochelatase, EPP in humans is associated with liver disease, hypertriglyceridemia, and a low l evel 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 homozy gous (fch/fch) or heterozygous (fch/+) for a point mutation in the ferroche latase gene and in wild-type controls (+/+), Livers of fch/fch mice show bi le duct proliferation and biliary fibrosis, but bile formation is not impai red. The free cholesterol content of fch/fch Livers is significantly increa sed 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 choles terol content in the very low density lipoprotein-sized fractions, whereas HDL cholesterol is reduced. The ratio of cholesteryl ester to free choleste rol 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 lecithi n: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 liv ers. In spite of this, biliary phospholipid/cholesterol secretion is reduce d relative to that of bile salts. It is postulated that an inability of bil e salts to stimulate lipid secretion adequately leads to formation of Lp-X in this noncholestatic condition. Distinct atherosclerotic lesions were fou nd in aged fch/fch mice. Thus, ferrochelatase deficiency in mice leads to l iver disease associated with altered hepatic lipid metabolism, a characteri stic hyperlipidemia, and development of atherosclerosis.