Nagasaka Hironori, Chiba Hitoshi, Hui Shu-Ping, Takikawa Hajime, Miida Takashi, Takayanagi Masaki, Yorifuji Tohru, Hasegawa Makoto, Ota Akemi, Hirano Ken-ichi, Kikuchi Hideaki, Tsukahara Hirokazu, Kobayashi Kunihiko
Division of Metabolism, Chiba Children's Hospital, Heta Cho, Midori-Ku, Chiba, Japan.
J Pediatr Gastroenterol Nutr. 2007 Jul;45(1):96-105. doi: 10.1097/MPG.0b013e3180331df9.
Lipoprotein metabolism in FIC1 deficiency due to ATP8B1 mutations has never been studied sufficiently. This study was performed to investigate the detailed lipoprotein metabolism in benign recurrent intrahepatic cholestasis (BRIC) caused by FIC1 deficiency.
Lipoprotein profile and major lipoprotein regulators such as lecithin:cholesterol acyltransferase (LCAT), hepatic triglyceride lipase (HTGL), lipoprotein lipase, and cholesteryl ester transfer protein in a Japanese patient with BRIC were serially examined during a bout of cholestasis. Liver expression of farnesoid X receptor (FXR), which suppresses high-density lipoprotein (HDL) generation, was also examined.
Hypercholesterolemia and lipoprotein X accumulation were never observed throughout this study. When the cholestasis was severe, triglyceride-rich low-density lipoprotein (LDL) accounted for most of the plasma lipoproteins whereas HDL was hardly detectable. Concurrently, activities of all regulators were decreased, together with decreases of the serum parameter for liver protein synthesis. In particular, suppressions of LCAT and HTGL activities were severe and greatly contributed to the appearance of triglyceride-rich LDL. As the cholestasis improved, this LDL gradually transformed into normal LDL with the recoveries of LCAT and HTGL activities. The activities of all regulators for the last 1 to 2 months were normal but HDL remained depleted. His liver showed low FXR expression compared with control livers.
The present study showed an appearance of triglyceride-rich LDL due to suppressions of LCAT and HTGL activities and a depletion of HDL that is not able to be explained by lipoprotein regulators or FXR in our patient.
因ATP8B1突变导致FIC1缺乏时的脂蛋白代谢尚未得到充分研究。本研究旨在调查由FIC1缺乏引起的良性复发性肝内胆汁淤积症（BRIC）中详细的脂蛋白代谢情况。
在一名日本BRIC患者的胆汁淤积发作期间，连续检测其脂蛋白谱以及主要脂蛋白调节因子，如卵磷脂胆固醇酰基转移酶（LCAT）、肝甘油三酯脂肪酶（HTGL）、脂蛋白脂肪酶和胆固醇酯转运蛋白。还检测了抑制高密度脂蛋白（HDL）生成的法尼醇X受体（FXR）的肝脏表达。
在整个研究过程中从未观察到高胆固醇血症和脂蛋白X蓄积。当胆汁淤积严重时，富含甘油三酯的低密度脂蛋白（LDL）占血浆脂蛋白的大部分，而HDL几乎检测不到。同时，所有调节因子的活性均降低，肝脏蛋白质合成的血清参数也降低。特别是，LCAT和HTGL活性的抑制很严重，对富含甘油三酯的LDL的出现起了很大作用。随着胆汁淤积的改善，这种LDL随着LCAT和HTGL活性的恢复逐渐转变为正常LDL。在最后1至2个月，所有调节因子的活性均正常，但HDL仍然缺乏。与对照肝脏相比，他的肝脏FXR表达较低。
本研究显示，在我们的患者中，由于LCAT和HTGL活性受到抑制，出现了富含甘油三酯的LDL，以及HDL缺乏，而脂蛋白调节因子或FXR无法解释这种情况。
