The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation.
The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation.
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DOI：
10.1002/hep.29273
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Hobbs HH
中科院分区：
文献类型：
--
作者：
BasuRay S;Smagris E;Cohen JC;Hobbs HH
Patatin样磷脂酶结构域包含蛋白3(PNPLA3)的一个序列变异(I148M)与脂肪肝密切相关，但其潜在机制仍不清楚。在这项研究中，我们使用敲入(KI)小鼠(Pnpla3148M/M)来研究甘油三酯(TG)和PNPLA3在肝脏脂滴(LDs)中积累的机制。Pnpla3148M/M和Pnpla3+/+小鼠在肝脏甘油三酯的合成、利用和分泌方面没有差异。这些结果与Pnpla3148M/M小鼠中TG的积聚是由LDS的TG动员受损引起的一致。与野生型(WT)小鼠相比，蔗糖喂养导致KI小鼠脂肪肝的PNPLA3蛋白增加幅度更大、持续时间更长。抑制蛋白酶体(Bortezomib)，但不抑制巨型自噬(3-甲基腺嘌呤)，显著增加WT小鼠PNPLA3的水平，与泛素化形式的蛋白质的出现相一致。在Pnpla3148M/M小鼠中，Bortezomib没有增加PNPLA3的水平，并且在这些动物中只看到微量的泛素化PNPLA3。结论：这些结果与148M突变破坏了PNPLA3的泛素化和蛋白酶体降解，导致PNPLA3-148M的积聚和LDS中TG的动员障碍的观点一致。(《肝病》2017；66：1111-1124)。
A sequence variation (I148M) in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) is strongly associated with fatty liver disease, but the underlying mechanism remains obscure. In this study, we used knock‐in (KI) mice (Pnpla3148M/M) to examine the mechanism responsible for accumulation of triglyceride (TG) and PNPLA3 in hepatic lipid droplets (LDs). No differences were found between Pnpla3148M/M and Pnpla3+/+ mice in hepatic TG synthesis, utilization, or secretion. These results are consistent with TG accumulation in the Pnpla3148M/M mice being caused by impaired TG mobilization from LDs. Sucrose feeding, which is required to elicit fatty liver in KI mice, led to a much larger and more persistent increase in PNPLA3 protein in the KI mice than in wild‐type (WT) mice. Inhibition of the proteasome (bortezomib), but not macroautophagy (3‐methyladenine), markedly increased PNPLA3 levels in WT mice, coincident with the appearance of ubiquitylated forms of the protein. Bortezomib did not increase PNPLA3 levels in Pnpla3148M/M mice, and only trace amounts of ubiquitylated PNPLA3 were seen in these animals. Conclusion: These results are consistent with the notion that the 148M variant disrupts ubiquitylation and proteasomal degradation of PNPLA3, resulting in accumulation of PNPLA3‐148M and impaired mobilization of TG from LDs. (Hepatology 2017;66:1111‐1124).
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