Identification of human long noncoding RNAs associated with nonalcoholic fatty liver disease and metabolic homeostasis

A growing number of long noncoding RNAs (lncRNAs) have emerged as vital metabolic regulators. However, most human lncRNAs are nonconserved and highly tissue specific, vastly limiting our ability to identify lncRNA regulators (hLMRs). In this study, we established a pipeline putative hLMRs that metabolically sensitive, disease relevant, population applicable. We first progressively processed multilevel transcriptome data select liver exhibit dynamic expression in the general population, show differential nonalcoholic fatty (NAFLD) respond dietary intervention small NAFLD cohort. then experimentally demonstrated responsiveness selected hepatic defined milieus liver-specific humanized mouse model. Furthermore, by extracting concise list protein-coding genes persistently correlated with populations, predicted specific function for each hLMR. Using gain- loss-of-function approaches mice well ectopic conventional mice, validated regulatory role one hLMR cholesterol metabolism coordinating an RNA-binding protein, PTBP1, modulate transcription synthesis genes. Our work overcame heterogeneity intrinsic enable efficient identification functional definition disease-relevant homeostasis.