Mounting genetic and clinical evidence supports the critical role of human long non-coding RNA metabolic regulators (hLMRs) in metabolic homeostasis. Yet, most human lncRNAs are non-conserved, hindering their functional characterization for clinical translation in a physiological context. In this study, we investigated the hypothesis that non-conserved hLMRs and mLMRs may have shared functions, forming functionally conserved LMRs (fcLMRs), which could define the physiological role of hLMRs in mice. To test this hypothesis, we have developed a sequence-independent strategy to select fcLMRs and validated their functional similarity in vivo. Knocking down mLMRs in mouse livers demonstrated that concurrent hLMR expression rescued their functions, confirming the pipeline's effectiveness. Using fcLMR1 (h/mLMR1) as an example, we further demonstrated that h/mLMR1 share similar in vivo metabolic function via a conserved docking mechanism. Specifically, both h/mLMR1 robustly regulated triglyceride levels through modulating the expression of a similar set of lipogenic genes in mice. Mechanistically, h/mLMR1 binds to PABPC1 via a short motif on either lncRNA that have divergent sequences but similar structures. The h/mLMR1-PABPC1 interaction inhibits protein translation, which subsequently activates an amino acid-mTOR-SREBP1 axis to regulate lipogenic gene expression. In light of the elevated expression of h/mLMR1 in humans and mice with hepatic steatosis, the PABPC1-binding motif on hLMR1 represents a potential non-conserved human drug target whose function can be fully validated in a physiologically relevant setting before any clinical studies. Hence our study indicates that fcLMRs represent a novel and prevalent biological phenomenon, and deep phenotyping of genetic mLMR mouse models constitutes a powerful approach to understand the pathophysiological role of hLMRs before translating them to actionable drug targets in humans.
C. Jiang: None. Z. Li: None. Y. Ma: None. H. Cao: None.
