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

Nat Commun. 2018 Jul 30;9(1):2986. doi: 10.1038/s41467-018-05383-2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Bile Acids and Salts / chemistry
  • CRISPR-Cas Systems
  • Calmodulin-Binding Proteins / metabolism
  • Disease Models, Animal
  • Fatty Liver
  • Gene Expression Profiling
  • HEK293 Cells
  • Hepatocytes / metabolism
  • Humans
  • Insulin Resistance
  • Lipogenesis / genetics*
  • Liver / physiopathology
  • Liver X Receptors / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Obesity / complications*
  • Obesity / genetics
  • Protein Interaction Mapping
  • Proteomics
  • RNA, Long Noncoding / genetics*
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Transcription, Genetic

Substances

  • Bile Acids and Salts
  • Calmodulin-Binding Proteins
  • Edf1 protein, mouse
  • Liver X Receptors
  • RNA, Long Noncoding
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1