Long noncoding RNA licensing of obesity-linked hepatic lipogenesis and NAFLD pathogenesis

Xu-Yun Zhao, Xuelian Xiong, Tongyu Liu, Lin Mi, Xiaoling Peng, Crystal Rui, Liang Guo, Siming Li, Xiaoying Li and Jiandie D. Lin ()
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Xu-Yun Zhao: University of Michigan Medical Center
Xuelian Xiong: University of Michigan Medical Center
Tongyu Liu: University of Michigan Medical Center
Lin Mi: University of Michigan Medical Center
Xiaoling Peng: University of Michigan Medical Center
Crystal Rui: University of Michigan Medical Center
Liang Guo: University of Michigan Medical Center
Siming Li: University of Michigan Medical Center
Xiaoying Li: Fudan University
Jiandie D. Lin: University of Michigan Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05383-2

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