CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level
CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level
复制标题
CELSR2 缺陷通过损害 UPR 和升高 ROS 水平来抑制肝细胞中的脂质积累
DOI：
10.1096/fj.202100786rr
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发表时间：
2021-10-01
期刊：
影响因子：
4.8
通讯作者：
Li, Jianshuang
中科院分区：
文献类型：
--
作者：
Tan, Junyang;Che, Yaping;Li, Jianshuang
钙粘蛋白EGF LAG七通道G型受体2（CELSR 2）是一种与果蝇（Drosophila flamingo）同源的哺乳动物细胞，属于钙粘蛋白亚家族。CELSR2主要在神经发育和纤毛极性中发挥作用。最近的研究表明，CELSR2基因与许多人类疾病相关，包括冠心病、特发性脊柱侧凸和癌症。全基因组关联研究数据显示，CELSR2-PSRC 1-SORT 1基因位点的SNP与循环脂质水平和冠状动脉疾病有很强的关联。然而，CELSR2在肝脏脂质代谢中的功能和潜在机制尚不清楚。在此，我们发现CELSR2表达在NAFLD/NASH患者和db/db小鼠的肝脏中降低。消除CELSR2可通过抑制脂质合成酶的表达而显著降低肝细胞中的脂质蓄积。此外，CELSR2缺乏可损害生理性未折叠蛋白反应（UPR），从而破坏ER稳态，并通过降低抗氧化剂表达而升高活性氧（ROS）水平。通过N-乙酰半胱氨酸处理清除ROS可以恢复CELSR 2敲除细胞的脂质积累减少。此外，CELSR2的缺失通过抑制细胞增殖和促进细胞凋亡而损害细胞存活。我们的研究结果揭示了CELSR2在调节脂质稳态和UPR中的新作用，表明CELSR2可能是非酒精性脂肪性肝病的新治疗靶点。
Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2), a mammalian orthologue of drosophila flamingo, belongs to the cadherin subfamily. CELSR2 mainly function in neural development and cilium polarity. Recent studies showed that the CELSR2 gene is related to many human diseases, including coronary artery disease, idiopathic scoliosis, and cancer. Genome-Wide Association Studies data showed that SNP in the CELSR2-PSRC1-SORT1 gene loci has a strong association with circulating lipid levels and coronary artery disease. However, the function and underlying mechanism of CELSR2 in hepatic lipid metabolism remain unknown. Here, we found that CELSR2 expression is decreased in the liver of NAFLD/NASH patients and db/db mice. Depletion of CELSR2 significantly decreased the lipid accumulation in hepatocytes by suppressing the expression of lipid synthesis enzymes. Moreover, CELSR2 deficiency impaired the physiological unfolded protein response (UPR), which damages the ER homeostasis, and elevates the reactive oxygen species (ROS) level by decreasing the antioxidant expression. Scavenging of ROS by N-acetylcysteine treatment could restore the decreased lipid accumulation of CELSR2 knockdown cells. Furthermore, CELSR2 loss impaired cell survival by suppressing cell proliferation and promoting apoptosis. Our results uncovered a new role of CELSR2 in regulating lipid homeostasis and UPR, suggesting CELSR2 may be a new therapeutic target for non-alcoholic fatty liver disease.