LncRNA DLEU2 regulates Sirtuins and mitochondrial respiratory chain complex IV: a novel pathway in obesity and DOHaD

ABSTRACT Long noncoding RNAs (lncRNAs) are commonly dysregulated in cancer but are mostly unknown for roles in metabolic regulation. Sirtuins, an epigenetic modulator class, regulate metabolic pathways. However, how sirtuins are regulated via lncRNA is unknown. In our findings, DLEU2, a lncRNA involved in primarily blood cancers, and sirtuins were both significantly decreased in the livers of high-fat high-fructose diet (HFD-HF) fed male mouse offspring (F1) whose mothers (F0) were either fed chow diet or HFD-HF during reproductive and pregnancy windows. Confirming this connection, upon silencing DLEU2, transcription levels of SIRT1 through 6 and translational levels of SIRT1, 3, 5, and 6 were significantly downregulated. Knockdown of DLEU2 also significantly decreased the protein level of cytochrome-c oxidase (complex IV, MTCO1) without altering other mitochondrial complexes, leading to increased reactive oxygen species production. Interestingly, in F1 livers, the protein level of MTCO1 was also significantly decreased under an HFD-HF diet or even under chow diet if the mother was exposed to HFD-HF. Our findings therefore reveal for the first time that a lncRNA can regulate sirtuins and a specific mitochondrial complex, furthermore suggesting a potential role of DLEU2 in metabolic disorders over one or more generations. HIGHLIGHTS Maternal diet can modulate hepatic lncRNA DLEU2 and its downstream regulators in offspring DLEU2 is required for specific sirtuin regulation and mitochondrial respiration chain complex IV expression Offspring liver depleted of DLEU2 show decreased mitochondrial respiration chain complex IV and specific sirtuins at transcriptional and translational levels