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.

中文翻译：

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CELSR2缺乏通过损害UPR和升高ROS水平来抑制肝细胞中的脂质积累

钙粘蛋白 EGF LAG 七通道 G 型受体 2 (CELSR2) 是果蝇火烈鸟的哺乳动物直向同源物，属于钙粘蛋白亚家族。CELSR2 主要在神经发育和纤毛极性中起作用。最近的研究表明，CELSR2基因与许多人类疾病有关，包括冠状动脉疾病、特发性脊柱侧弯和癌症。全基因组关联研究数据显示CELSR2-PSRC1-SORT1 中的SNP基因位点与循环血脂水平和冠状动脉疾病密切相关。然而，CELSR2 在肝脏脂质代谢中的功能和潜在机制仍然未知。在这里，我们发现 CELSR2 表达在 NAFLD/NASH 患者和 db/db 小鼠的肝脏中降低。CELSR2 的消耗通过抑制脂质合成酶的表达显着降低了肝细胞中的脂质积累。此外，CELSR2 缺乏会损害生理未折叠蛋白反应 (UPR)，从而破坏内质网稳态，并通过降低抗氧化剂表达来提高活性氧 (ROS) 水平。通过 N-乙酰半胱氨酸处理清除 ROS 可以恢复 CELSR2 敲低细胞减少的脂质积累。此外，CELSR2 缺失通过抑制细胞增殖和促进细胞凋亡来损害细胞存活。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肝疾病的新治疗靶点。