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 biletype 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. Erythropoietic protoporphyria (EPP) is an inherited disorder of heme synthesis caused by deficiency of the mitochondrial enzyme ferrochelatase (EC 4.99.1.1), responsible for insertion of iron into protoporphyrin (PP) (1). Impaired ferrochelatase activity in humans with EPP results in increased PP concentrations in erythrocytes, blood, liver, and feces (1). Skin lesions after exposure to sunlight represent the hallmark of EPP. Liver disease is one of the complications that may occur in patients with EPP but hepatic manifestations of EPP are diverse (1, 2). About 40 different mutations in the human ferrochelatase gene have been described so far (3). It appears that only mutations that give rise to severe deficiencies of enzyme activity predispose to development of liver disease for which transplantation is indicated (4).Elevated plasma triglyceride levels and low levels of high density lipoprotein (HDL) cholesterol have been reported in EPP patients (...

BaCKgRoUND aND aIMS:Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2-arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis, a disease so far lacking effective pharmacological therapy. appRoaCH aND ReSUltS: To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild-type (WT) and knockout (MGL −/− ) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout (Mdr2 −/− ) mouse model of sclerosing cholangitis. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression, and western blot characterization of BA and FA synthesis/ transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL −/− mice were protected from DDC-induced biliary fibrosis and inflammation with reduced serum liver enzymes and increased FA/BA metabolism and β-oxidation. Notably, pharmacological ( JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2 −/− mice from spontaneous liver injury, with improved liver enzymes, inflammation, and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E 2 accumulation in the intestine and up-regulates peroxisome proliferator-activated receptors alpha and gamma activity, thus reducing inflammation.CoNClUSIoNS: Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis.

6-Mercaptopurine (6-MP) maintains remission in pediatric Crohn's disease (CD). Azathioprine, a prodrug of 6-MP, is used for maintenance of remission of CD in Europe. We evaluated to what extent azathioprine is used in newly diagnosed pediatric CD patients and whether maintenance of remission differed between patients using azathioprine or not. Charts of children (diagnosed 1998Y2003, follow-up Q 18 mo) were reviewed. Active disease was defined as Pediatric Crohn's Disease Activity Index (PCDAI) greater than 10 or systemic corticosteroid use. Remission was defined as PCDAI 10 or less without use of corticosteroids. Eighty-eight children (55M/33F, age 12 T 3 yr) were included. Seventy-two (82%) patients received azathioprine during the follow-up period (38 T 17 mo). Patients diagnosed after 2000 received azathioprine significantly earlier during the course of disease compared with those diagnosed earlier (median, at 233 vs. 686 days; P G 0.05). At initial presentation, moderate-severe disease activity and prescription of corticosteroids were more prevalent in patients using azathioprine compared with nonazathioprine patients (75% vs. 52%; P G 0.05; and 89% vs. 58%; P G 0.005, respectively). Duration of corticosteroid use was longer in patients receiving azathioprine (232 vs. 168 days; P G 0.005). Median maintenance of first remission in patients who initially used corticosteroids, however, was longer in patients receiving azathioprine compared with nonazathioprine patients (PCDAI, 544 vs. 254 days, P = 0.08; corticosteroid free, 575 vs. 259 days, P G 0.05, respectively). We conclude that, since 2000, azathioprine is being introduced earlier in the treatment of newly diagnosed pediatric CD patients. The use of azathioprine is associated with prolonged maintenance of the first remission.

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