Hepatocyte-Specific Depletion of UBXD8 Induces Periportal Steatosis in Mice Fed a High-Fat Diet
Hepatocyte-Specific Depletion of UBXD8 Induces Periportal Steatosis in Mice Fed a High-Fat Diet
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DOI：
10.1371/journal.pone.0127114
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发表时间：
2015-05-13
期刊：
影响因子：
3.7
通讯作者：
Fujimoto, Toyoshi
中科院分区：
文献类型：
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作者：
Imai, Norihiro;Suzuki, Michitaka;Fujimoto, Toyoshi
我们先前表明，UBXD 8在肝癌细胞系中脂化ApoB的蛋白酶体降解中起关键作用。在本研究中，我们的目的是在体内研究UBXD 8在肝脏中的功能。为此，产生肝细胞特异性UBXD 8敲除（UBXD 8-LKO）小鼠。它们被喂食正常或高脂肪饮食，并与同窝对照小鼠的表型进行比较。在培养物中分析从UBXD 8-LKO和对照小鼠获得的肝细胞。高脂饮食26周后，UBXD 8-LKO小鼠在门静脉周围区域表现出大泡性脂肪变性，在静脉周围区域表现出小泡性脂肪变性，而对照小鼠仅在静脉周围区域表现出脂肪变性。此外，高脂饮食的UBXD 8-LKO小鼠的血清甘油三酯和VLDL浓度显著低于对照小鼠。Triton WR-1339注射研究显示，UBXD 8-LKO小鼠肝细胞的VLDL分泌减少。在培养的原代肝细胞中重现了UBXD 8耗竭后ApoB分泌的减少。仅在UBXD 8缺失肝细胞中观察到脂化ApoB在脂滴中的蓄积。结果表明，肝细胞中UBXD 8的消耗抑制了VLDL的分泌，并且当小鼠被喂食高脂肪饮食时可能导致门静脉周围脂肪变性。这是第一次证明细胞内ApoB降解机制的异常可以引起脂肪变性，并提供了一个有用的模型，门静脉周围脂肪变性，这发生在几个人类疾病。
We showed previously that UBXD8 plays a key role in proteasomal degradation of lipidated ApoB in hepatocarcinoma cell lines. In the present study, we aimed to investigate the functions of UBXD8 in liver in vivo. For this purpose, hepatocyte-specific UBXD8 knockout (UBXD8-LKO) mice were generated. They were fed with a normal or high-fat diet, and the phenotypes were compared with those of littermate control mice. Hepatocytes obtained from UBXD8-LKO and control mice were analyzed in culture. After 26 wk of a high-fat diet, UBXD8-LKO mice exhibited macrovesicular steatosis in the periportal area and microvesicular steatosis in the perivenular area, whereas control mice exhibited steatosis only in the perivenular area. Furthermore, UBXD8-LKO mice on a high-fat diet had significantly lower concentrations of serum triglyceride and VLDL than control mice. A Triton WR-1339 injection study revealed that VLDL secretion from hepatocytes was reduced in UBXD8-LKO mice. The decrease of ApoB secretion upon UBXD8 depletion was recapitulated in cultured primary hepatocytes. Accumulation of lipidated ApoB in lipid droplets was observed only in UBXD8-null hepatocytes. The results showed that depletion of UBXD8 in hepatocytes suppresses VLDL secretion, and could lead to periportal steatosis when mice are fed a high-fat diet. This is the first demonstration that an abnormality in the intracellular ApoB degradation mechanism can cause steatosis, and provides a useful model for periportal steatosis, which occurs in several human diseases.