INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Université Paris Diderot, site Bichat, Centre de reference des maladies inflammatoires des voies biliaires, service d’Hépatologie-Gastroentérologie, Hôpital Saint Antoine, Paris, France.
Gastroenterology. 2011 Oct;141(4):1509-19, 1519.e1-3. doi: 10.1053/j.gastro.2011.06.078. Epub 2011 Jul 14.
BACKGROUND & AIMS: Chronic, progressive hepatobiliary disease is the most severe complication of erythropoietic protoporphyria (EPP) and can require liver transplantation, although the mechanisms that lead to liver failure are unknown. We characterized protoporphyrin-IX (PPIX)-linked hepatobiliary disease in BALB/c and C57BL/6 (Fechm1Pas) mice with mutations in ferrochelatase as models for EPP.
Fechm1Pas and wild-type (control) mice were studied at 12-14 weeks of age. PPIX was quantified; its distribution in the liver, serum levels of lipoprotein-X, liver histology, contents of bile salt and cholesterol phospholipids, and expression of genes were compared in mice of the BALB/c and C57BL/6 backgrounds. The in vitro binding affinity of PPIX for bile components was determined.
Compared with mice of the C57BL/6 background, BALB/c Fechm1Pas mice had a more severe pattern of cholestasis, fibrosis with portoportal bridging, bile acid regurgitation, sclerosing cholangitis, and hepatolithiasis. In C57BL/6 Fechm1Pas mice, PPIX was sequestrated mainly in the cytosol of hepatocytes and Kupffer cells, whereas, in BALB/c Fechm1Pas mice, PPIX was localized within enlarged bile canaliculi. Livers of C57BL/6 Fechm1Pas mice were protected through a combination of lower efflux of PPIX and reduced synthesis and export of bile acid.
PPIX binds to bile components and disrupts the physiologic equilibrium of phospholipids, bile acids, and cholesterol in bile. This process might be involved in pathogenesis of sclerosing cholangitis from EPP; a better understanding might improve diagnosis and development of reagents to treat or prevent liver failure in patients with EPP.
慢性进行性肝胆疾病是红细胞生成性原卟啉症（EPP）最严重的并发症，可能需要进行肝移植，尽管导致肝衰竭的机制尚不清楚。我们以亚铁螯合酶突变的 BALB/c 和 C57BL/6（Fechm1Pas）小鼠为模型，对原卟啉 IX（PPIX）相关的肝胆疾病进行了研究。
在 12-14 周龄时，对 Fechm1Pas 和野生型（对照）小鼠进行了研究。比较了两种小鼠背景下 PPIX 的含量；其在肝脏中的分布；血清脂蛋白-X 水平；肝组织学；胆汁盐和胆固醇磷脂含量；以及基因表达。还测定了 PPIX 与胆汁成分的体外结合亲和力。
与 C57BL/6 背景的小鼠相比，BALB/c Fechm1Pas 小鼠表现出更严重的胆汁淤积模式、伴有门脉间桥接的纤维化、胆汁酸反流、硬化性胆管炎和胆石症。在 C57BL/6 Fechm1Pas 小鼠中，PPIX 主要被隔离在肝细胞和枯否细胞的细胞质中，而在 BALB/c Fechm1Pas 小鼠中，PPIX 则定位于增大的胆小管内。C57BL/6 Fechm1Pas 小鼠的肝脏通过降低 PPIX 的外流以及减少胆汁酸的合成和分泌而受到保护。
PPIX 与胆汁成分结合，并破坏了胆汁中磷脂、胆汁酸和胆固醇的生理平衡。这一过程可能与 EPP 引起的硬化性胆管炎发病机制有关；更好地了解这一过程可能有助于改善 EPP 患者的诊断，并开发出治疗或预防肝衰竭的试剂。
