LDLR, as the uptake receptor of low-density lipoprotein, plays a crucial role in lipid metabolism. However, the detailed mechanism by which LDLR affects hepatic triglyceride (TG) accumulation has rarely been reported. Here, we found that knockdown of LDLR effectively mitigated PA-induced TG accumulation. Further analysis revealed that the expression of LDLR was controlled by SREBP2 directly and indirectly. On one hand, transcription factor SREBP2 activated the transcription of LDLR directly. On the other hand, SREBP2 indirectly regulated LDLR by increasing the transcription of lncRNA LDLR-AS in fish. Mechanism analysis found that LDLR-AS functioned as an RNA scaffold to recruit heterogeneous nuclear ribonucleoprotein R (hnRNPR) to the 5’ UTR region of LDLR mRNA, which stabilized LDLR mRNA at the post-transcription level. In conclusion, our study demonstrates that increased LDLR transcription and mRNA stability is regulated by SREBP2 directly or indirectly, and promotes hepatic TG accumulation by endocytosing LDL in fish.

LDLR作为低密度脂蛋白的摄取受体，在脂质代谢中起着至关重要的作用。然而，LDLR 影响肝脏甘油三酯 (TG) 积累的详细机制却鲜有报道。在这里，我们发现 LDLR 的敲低有效地减轻了 PA 诱导的 TG 积累。进一步分析表明，LDLR的表达受SREBP2直接和间接控制。一方面，转录因子SREBP2直接激活了LDLR的转录。另一方面，SREBP2 通过增加鱼中 lncRNA LDLR-AS 的转录间接调节 LDLR。机制分析发现，LDLR-AS 作为 RNA 支架将异质核核糖核蛋白 R (hnRNPR) 募集到LDLR mRNA 的 5' UTR 区域，从而稳定LDLR转录后水平的 mRNA。总之，我们的研究表明，增加的 LDLR 转录和 mRNA 稳定性受 SREBP2 直接或间接调节，并通过内吞鱼类中的 LDL 促进肝脏 TG 积累。