A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice.
Long non-coding RNAs (lncRNAs) constitute a significant portion of mammalian genome, yet the physiological importance of lncRNAs is largely unknown. Here, we identify a liver-enriched lncRNA in mouse that we term liver-specific triglyceride regulator (lncLSTR). Mice with a liver-specific depletion of lncLSTR exhibit a marked reduction in plasma triglyceride levels. We show that lncLSTR depletion enhances apoC2 expression, leading to robust lipoprotein lipase activation and increased plasma triglyceride clearance. We further demonstrate that the regulation of apoC2 expression occurs through an FXR-mediated pathway. LncLSTR forms a molecular complex with TDP-43 to regulate expression of Cyp8b1, a key enzyme in the bile acid synthesis pathway, and engenders an in vivo bile pool that induces apoC2 expression through FXR. Finally, we demonstrate that lncLSTR depletion can reduce triglyceride levels in a hyperlipidemia mouse model. Taken together, these data support a model in which lncLSTR regulates a TDP-43/FXR/apoC2-dependent pathway to maintain systemic lipid homeostasis.
Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Ping
P
Li
Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Xiangbo
X
Ruan
Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Ling
L
Yang
Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Kurtis
K
Kiesewetter
Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, PR China.
Yi
Y
Zhao
Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, PR China.
Haitao
H
Luo
Proteomics Core, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Yong
Y
Chen
Proteomics Core, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Marjan
M
Gucek
Systems Biology Center, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Jun
J
Zhu
Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA. Electronic address: haiming.cao@nih.gov.
Haiming
H
Cao
D000818:Animals; D053304:Apolipoprotein C-II / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006949:Hyperlipidemias / Q000097:blood / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008071:Lipoprotein Lipase / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D062085:RNA, Long Noncoding / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013253:Steroid 12-alpha-Hydroxylase / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D053304:Apolipoprotein C-II; D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D062085:RNA, Long Noncoding; D014280:Triglycerides; D013253:Steroid 12-alpha-Hydroxylase; D008071:Lipoprotein Lipase