Regulation of Systemic Energy Metabolism by a Human-Specific Long Noncoding RNA In Vivo

2018 
Long non-coding RNAs (lncRNAs) are widely expressed in mammals and play critical roles in a broad array of physiological processes. We have recently demonstrated that lncRNAs sense and regulate lipid and glucose metabolism in mice. However, it remains to be determined whether human lncRNAs regulate metabolism in vivo and whether they play a role in the pathogenesis of human metabolic disorders. The lack of knowledge of lncRNA’s functions in human metabolism is partly caused by the extremely low sequence conservation between human and mouse lncRNAs, which makes it difficult to apply the functional information of mouse lncRNAs to human physiology. To overcome this limitation, we have produced liver-specific humanized mice in which over 80% of mouse hepatocytes in the liver can be replaced by human ones and have confirmed that human metabolic genes in these mice maintain proper responses to metabolic cues. Using the liver-specific humanized mice, we identify a Fasting induced, Human-specific, and Liver-enriched lncRNA (lncFHL). Knocking down of lncFHL in humanized mice results in decreased expression of genes in Peroxisome Proliferator Activated Receptor Alpha (PPARalpha) pathway, which leads to decreased fasting plasma glucose and ketone levels. We further find that lncFHL interacts with and affects the mRNA interactions of HuR, a RNA binding protein that suppresses hepatic PPARalpha pathway in human. Finally, by analyzing published genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) data, we find the hepatic expressions of lncFHL are associated with human metabolic diseases including diabetes and coronary artery disease . These studies not only provide a proof of principle that the humanized mice could sever as a suitable model to study the metabolic function of human lncRNAs but also demonstrate that regulatory mechanism mediated by human-specific lncRNAs contributes significantly to physiological and pathophysiological metabolic homeostasis. Disclosure X. Ruan: None. P. Li: None. H. Cao: None.
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