Long noncoding RNA FLRL2 alleviated nonalcoholic fatty liver disease through Arntl‐Sirt1 pathway

Abstract

Nonalcoholic fatty liver disease (NAFLD), which has an unknown pathogenesis and lacks a curative treatment, is becoming more prevalent. A previous long noncoding RNA (lncRNA) profiling analysis revealed a potential role for fatty liver–related lncRNA 2 (FLRL2) in the pathogenesis of NAFLD. To further understand the role of FLRL2 in NAFLD and explore its therapeutic value, both in vivo and in vitro NAFLD models were constructed. Small interfering RNA and small hairpin RNA interference and adenovirus transfection were adopted to manipulate the expressions of FLRL2, aryl‐hydrocarbon receptor nuclear translocator‐like (Arntl), and sirtuin 1 (Sirt1) expression. Steatosis was evaluated through histologic staining with hematoxylin and eosin and oil red O and also by quantitative triglyceride measurements. FLRL2 is a widely distributed nuclear lncRNA that is down‐regulated in NAFLD. Overexpression of FLRL2 resolved steatosis, lipogenesis, inflammation, and endoplasmic reticulum (ER) stress in NAFLD, and down‐regulation of FLRL2 resulted in the opposite effects. Sequence analysis demonstrated that FLRL2 was located in the intronic region of the Arntl gene, and a luciferase assay showed transcriptional activation of the Arntl gene upon FLRL2 overexpression. A similar expression pattern and synergistic effect of Arntl manipulation was observed in NAFLD in vitro. Inhibition of Arntl partially reversed the steatosis amelioration induced by FLRL2 overexpression. Downstream Sirt1 was also inhibited in NAFLD and influenced by both FLRL2 and Arntl. In NAFLD mice, FLRL2 enhancement alleviated steatosis, activated the Arntl‐Sirt1 axis, and inhibited lipogenesis, ER stress, and inflammation, providing preliminary evidence of the benefits of FLRL2‐mediated gene therapy in NAFLD.—Chen, Y., Chen, X., Gao, J., Xu, C., Xu, P., Li, Y., Zhu, Y., Yu, C. Long noncoding RNA FLRL2 alleviated nonalcoholic fatty liver disease through Arntl‐Sirt1 pathway. FASEB J. 33, 11411–11419 (2019). http://www.fasebj.org

Long Non-Coding RNAs in Liver Cancer and Nonalcoholic Steatohepatitis

“…Overexpression of FLRL2 in vitro alleviated lipid accumulation, inflammation, and ER stress in cultured mouse liver cells, whereas knockdown of FLRL2 led to accumulation of cellular lipids [125]. Furthermore, adenovirus-mediated overexpression of FLRL2 in high fat diet-fed mice resulted in activation of the Arntl-Sirtuin 1 pathway, inhibition of lipogenesis and reduction of hepatic steatosis, highlighting the therapeutic potential of FLRL2 in NAFLD [125].…”

“…The lncRNA fatty liver-related lncRNA 2 (FLRL2) is a nuclear-localized lncRNA that is down-regulated in the NAFLD mouse model, located in the intronic region of the aryl hydrocarbon receptor nuclear translocator-like (Arntl) gene and implicated in the regulation of Arntl in cis [124]. Overexpression of FLRL2 in vitro alleviated lipid accumulation, inflammation, and ER stress in cultured mouse liver cells, whereas knockdown of FLRL2 led to accumulation of cellular lipids [125]. Furthermore, adenovirus-mediated overexpression of FLRL2 in high fat diet-fed mice resulted in activation of the Arntl-Sirtuin 1 pathway, inhibition of lipogenesis and reduction of hepatic steatosis, highlighting the therapeutic potential of FLRL2 in NAFLD [125].…”

Role of long non‐coding RNAs in adipogenesis: State of the art and implications in obesity and obesity‐associated diseases

“…The lncRNA H19 was also upregulated in NAFLD murine models, and again its silencing reduced lipid accumulation in hepatocytes 252 . On the contrary, overexpression of the lncRNA FLRL2 in vivo in murine NAFLD models resolved steatosis, lipogenesis, and inflammation 253 . Similarly, Meg3 was downregulated in HFD mice, and acting as ceRNA for miR‐21 it could help alleviate lipid over‐deposition 254 …”

Long-Term Effects of Very Low Dose Particle Radiation on Gene Expression in the Heart: Degenerative Disease Risks

“…Of these 10 genes, 8 were upregulated (Dbp, Gstt2, Pik3ip1, Tspan4, Tcap, Stc2, P2rx7, and Nr1d2) and 2 were downregulated (Errfi1 and Arntl). These 10 common genes are implicated in the modulation of circadian rhythms [20][21][22], regulation of muscle cell differentiation and locomotor activity [23], cardiac hypertrophy [24], metabolism [23,25,26], oxidative stress [27][28][29], inflammation [30][31][32], and tumorigenesis [23,[33][34][35][36].…”