Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA.
Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200030, China.
Nat Commun. 2018 Jul 30;9(1):2986. doi: 10.1038/s41467-018-05383-2.
Hepatic lipogenesis is aberrantly induced in nonalcoholic fatty liver disease (NAFLD) via activation of the LXR-SREBP1c pathway. To date, a number of protein factors impinging on the transcriptional activity of LXR and SREBP1c have been elucidated. However, whether this regulatory axis interfaces with long noncoding RNAs (lncRNAs) remains largely unexplored. Here we show that hepatic expression of the lncRNA Blnc1 is strongly elevated in obesity and NAFLD in mice. Blnc1 is required for the induction of SREBP1c and hepatic lipogenic genes in response to LXR activation. Liver-specific inactivation of Blnc1 abrogates high-fat diet-induced hepatic steatosis and insulin resistance and protects mice from diet-induced nonalcoholic steatohepatitis. Proteomic analysis of the Blnc1 ribonucleoprotein complex identified EDF1 as a component of the LXR transcriptional complex that acts in concert with Blnc1 to activate the lipogenic gene program. These findings illustrate a lncRNA transcriptional checkpoint that licenses excess hepatic lipogenesis to exacerbate insulin resistance and NAFLD.
肝脂肪生成在非酒精性脂肪性肝病 (NAFLD) 中通过 LXR-SREBP1c 途径的激活而异常诱导。迄今为止，已经阐明了许多影响 LXR 和 SREBP1c 转录活性的蛋白质因子。然而，该调节轴是否与长链非编码 RNA (lncRNA) 相互作用在很大程度上仍未得到探索。在这里，我们发现 lncRNA Blnc1 在肥胖和 NAFLD 小鼠中的肝脏表达强烈升高。Blnc1 是 LXR 激活后诱导 SREBP1c 和肝脏脂肪生成基因所必需的。Blnc1 的肝特异性失活可消除高脂肪饮食诱导的肝脂肪变性和胰岛素抵抗，并保护小鼠免受饮食诱导的非酒精性脂肪性肝炎。Blnc1 核糖核蛋白复合物的蛋白质组学分析鉴定出 EDF1 是 LXR 转录复合物的一个组成部分，它与 Blnc1 协同作用激活脂肪生成基因程序。这些发现说明了 lncRNA 转录检查点，该检查点许可过度的肝脂肪生成以加重胰岛素抵抗和 NAFLD。
