Increased LDL receptor by SREBP2 or SREBP2-induced lncRNA LDLR-AS promotes triglyceride accumulation in fish

Xiufei Cao; Wei Fang; Xueshan Li; Xiuneng Wang; Kangsen Mai; Qinghui Ai

doi:10.1016/j.isci.2022.104670

Increased LDL receptor by SREBP2 or SREBP2-induced lncRNA LDLR-AS promotes triglyceride accumulation in fish

iScience. 2022 Jun 26;25(7):104670. doi: 10.1016/j.isci.2022.104670. eCollection 2022 Jul 15.

Authors

Xiufei Cao¹, Wei Fang¹, Xueshan Li¹, Xiuneng Wang¹, Kangsen Mai^{1

2}, Qinghui Ai^{1

2}

Affiliations

¹ Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, Shandong 266003, People's Republic of China.
² Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, Shandong 266237, People's Republic of China.

Abstract

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.

Keywords: Biological sciences; Cell biology; Functional aspects of cell biology; Zoology.