507-P: Human Liver-Specific Regulation of Lipogenesis by Long Noncoding RNA hLMR1

Hepatic de novo lipogenesis (DNL) significantly contributes to circulating triglycerides in the presence of high carbohydrate diets, making liver-specific inhibition of DNL an attractive strategy for relieving hypertriglyceridemia to control coronary artery disease (CAD) risk. We recently identified a human lncRNA, hLMR1 (Gene symbol: LOC100507389), which promotes hepatic cholesterol synthesis. Our unpublished follow-up studies demonstrated that genetic variants associated with elevated blood triglyceride levels predispose carbohydrates-induced hLMR1 expression, and hLMR1 positively regulates the expression of glycolytic and lipogenic genes. The aim of this work is to define how hLMR1 regulates glycolysis and lipogenesis. ChiRP-Seq, a high-throughput sequencing method to discover regions of the genome that are bound by a specific RNA, was performed using hLMR1 targeting probes in human liver tissues. hLMR1 target genes were measured in cultured human hepatocytes and a humanized liver mouse model upon knocking down of hLMR1. One-way ANOVA is being used for the statistical analysis. We found that hLMR1 is robustly upregulated by carbohydrates and knocking down of hLMR1 in humanized livers resulted in decreased expression of genes in the glycolysis and lipogenesis pathway. Furthermore, hLMR1, and its interacting protein, PTBP1, positively regulate the expression and interact with an enhancer region of ChREBP-β, a known transcription factor strongly associated with hepatic lipogenesis and blood triglyceride levels in humans. As a human liver-specific lncRNA, hLMR1 positively regulates glycolysis and lipogenesis, likely by inducing the expression of ChREBP-β. Our future work will further explore the role of this hLMR1-ChREBP-β signaling pathway in high carbohydrate diet-induced fatty liver diseases and hypertriglyceridemia using the humanized liver mouse model.