Human GDPD3 overexpression promotes liver steatosis by increasing lysophosphatidic acid production and fatty acid uptake
Human GDPD3 overexpression promotes liver steatosis by increasing lysophosphatidic acid production and fatty acid uptake
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DOI：
10.1194/jlr.ra120000760
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发表时间：
2020-07-01
影响因子：
6.5
通讯作者：
Parks, John S.
中科院分区：
文献类型：
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作者：
Key, Chia-Chi C.;Bishop, Andrew C.;Parks, John S.
甘油磷酸途径产生超过90%的肝脏三酰甘油(TAG)。该途径的中间产物LysoPA由甘油-3-磷酸酰基转移酶产生。最近克隆的甘油磷酸二酯磷酸二酯酶结构域3(GDPD3)含有溶血磷脂酶D活性，能从溶血磷脂中产生溶血磷脂酶A。人类GDPD3是否在肝脏TAG内稳态中起作用尚不清楚。我们假设人类GDPD3增加了LysoPA的产生和在甘油磷酸途径中的利用率，促进了Tag的生物合成。为了验证我们的假设，我们用编码肝细胞特异性白蛋白启动子的腺相关病毒感染C57BL/6J小鼠，该病毒驱动GFP(对照)或标记的人GDPD3过表达，并给小鼠喂食食物或西方饮食以诱导肝骨肉瘤病。肝脏人GDPD3过表达诱导小鼠肝细胞和肝脏中LysoPA的产生，增加FA的摄取和掺入TAG，最终加剧西方饮食诱导的肝脏脂肪变性。我们的结果还表明，与未发生脂肪变性的个体相比，肝脏脂肪变性个体的GDPD3mRNA水平升高。总之，这些发现表明，GDPD3表达上调可能在肝脏TAG积聚中发挥关键作用，并可能代表治疗肝脏脂肪变性的分子靶点。
The glycerol phosphate pathway produces more than 90% of the liver triacylglycerol (TAG). LysoPA, an intermediate in this pathway, is produced by glycerol-3-phosphate acyltransferase. Glycerophosphodiester phosphodiesterase domain containing 3 (GDPD3), whose gene was recently cloned, contains lysophospholipase D activity, which produces LysoPA from lysophospholipids. Whether human GDPD3 plays a role in hepatic TAG homeostasis is unknown. We hypothesized that human GDPD3 increases LysoPA production and availability in the glycerol phosphate pathway, promoting TAG biosynthesis. To test our hypothesis, we infected C57BL/6J mice with adeno-associated virus encoding a hepatocyte-specific albumin promoter that drives GFP (control) or FLAG-tagged humanGDPD3overexpression and fed the mice chow or a Western diet to induce hepatosteatosis. Hepatic humanGDPD3overexpression induced LysoPA production and increased FA uptake and incorporation into TAG in mouse hepatocytes and livers, ultimately exacerbating Western diet-induced liver steatosis. Our results also showed that individuals with hepatic steatosis have increasedGDPD3mRNA levels compared with individuals without steatosis. Collectively, these findings indicate that upregulation of GDPD3 expression may play a key role in hepatic TAG accumulation and may represent a molecular target for managing hepatic steatosis.