Abstract
BackgroundThe majority of mammalian genome is composed of non-coding regions, where numerous long non-coding RNAs (lncRNAs) are transcribed. Although lncRNAs have been identified to regulate fundamental biological processes, most of their functions remain unknown, especially in metabolic homeostasis. Analysis of our recent genome-wide screen reveals that Gm15441, a thioredoxin-interacting protein (Txnip) antisense lncRNA, is the most robustly induced lncRNA in the fasting mouse liver. Antisense lncRNAs are known to regulate their sense gene expression. Given that Txnip is a critical metabolic regulator of the liver, we aimed to investigate the role of Gm15441 in the regulation of Txnip and liver metabolism.MethodsWe examined the response of Gm15441 and Txnip under in vivo metabolic signals such as fasting and refeeding, and in vitro signals such as insulin and key metabolic transcription factors. We investigated the regulation of Txnip expression by Gm15441 and the underlying mechanism in mouse hepatocytes. Using adenovirus-mediated liver-specific overexpression, we determined whether Gm15441 regulates Txnip in the mouse liver and modulates key aspects of liver metabolism.ResultsWe found that the expression levels of Gm15441 and Txnip showed a similar response pattern to metabolic signals in vivo and in vitro, but that their functions were predicted to be opposite. Furthermore, we found that Gm15441 robustly reduced Txnip protein expression in vitro through sequence-specific regulation and translational inhibition. Lastly, we confirmed the Txnip inhibition by Gm15441 in vivo (mice) and found that Gm15441 liver-specific overexpression lowered plasma triglyceride and blood glucose levels and elevated plasma ketone body levels.ConclusionsOur data demonstrate that Gm15441 is a potent Txnip inhibitor and a critical metabolic regulator in the liver. This study reveals the therapeutic potential of Gm15441 in treating metabolic diseases.
Highlights
The majority of mammalian genome is composed of non-coding regions, where numerous long non-coding RNAs are transcribed
We found that the messenger RNAs (mRNAs) and protein expression levels of thioredoxin-interacting protein (Txnip) were significantly increased under fasting conditions and decreased after refeeding (Fig. 1C, D)
Our study demonstrated that long non-coding RNAs (lncRNAs) Gm15441 dynamically responds to in vivo and in vitro metabolic signals in a similar pattern to its sense gene Txnip
Summary
The majority of mammalian genome is composed of non-coding regions, where numerous long non-coding RNAs (lncRNAs) are transcribed. LncRNAs have been identified to regulate fundamental biologi‐ cal processes, most of their functions remain unknown, especially in metabolic homeostasis. Antisense lncRNAs are known to regulate their sense gene expres‐ sion. LncRNAs can perform many functions through diverse mechanisms, including transcriptional regulation in cis or trans, organization of nuclear domains, and regulation of proteins and other RNA molecules [9]. The newly recognized roles of lncRNAs across all taxa provide a novel perspective on the centrality of RNA in gene regulation [7]. The function and biological relevance of lncRNAs in metabolic homeostasis remain enigmatic [12]
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