Loss of Hilnc prevents diet-induced hepatic steatosis through binding of IGF2BP2

Yiao Jiang; Jiayin Peng; Jiawen Song; Juan He; Man Jiang; Jia Wang; Liya Ma; Yuang Wang; Moubin Lin; Hailong Wu; Zhao Zhang; Dong Gao; Yun Zhao

doi:10.1038/s42255-021-00488-3

Loss of Hilnc prevents diet-induced hepatic steatosis through binding of IGF2BP2

Yiao Jiang, Jiayin Peng, Jiawen Song, Juan He, Man Jiang, Jia Wang, Liya Ma, Yuang Wang, Moubin Lin, Hailong Wu, Zhao Zhang, Dong Gao, Yun Zhao

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

The Hedgehog (Hh) signalling pathway plays a critical role in regulating liver lipid metabolism and related diseases. However, the underlying mechanisms are poorly understood. Here, we show that the Hh signalling pathway induces a previously undefined long non-coding RNA (Hilnc, Hedgehog signalling-induced long non-coding RNA), which controls hepatic lipid metabolism. Mutation of the Gli-binding sites in the Hilnc promoter region (Hilnc^BM/BM) decreases the expression of Hilnc in vitro and in vivo. Hilnc^BM/BM and Hilnc-knockout mice are resistant to diet-induced obesity and hepatic steatosis through attenuation of the peroxisome proliferator-activated receptor signalling pathway, as Hilnc directly interacts with IGF2BP2 to enhance Pparγ mRNA stability. Furthermore, we identify a potential functional human homologue of Hilnc, h-Hilnc, which has a similar function in regulating cellular lipid metabolism. These findings uncover a critical role of the Hh-Hilnc–IGF2BP2 signalling axis in lipid metabolism and suggest a potential therapeutic target for the treatment of diet-induced hepatic steatosis.

Original language	English (US)
Pages (from-to)	1569-1584
Number of pages	16
Journal	Nature Metabolism
Volume	3
Issue number	11
DOIs	https://doi.org/10.1038/s42255-021-00488-3
State	Published - Nov 2021

ASJC Scopus subject areas

Physiology (medical)
Internal Medicine
Endocrinology, Diabetes and Metabolism
Cell Biology

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10.1038/s42255-021-00488-3

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@article{4b47e559ab324d0cbeb786fe8f4ce891,

title = "Loss of Hilnc prevents diet-induced hepatic steatosis through binding of IGF2BP2",

abstract = "The Hedgehog (Hh) signalling pathway plays a critical role in regulating liver lipid metabolism and related diseases. However, the underlying mechanisms are poorly understood. Here, we show that the Hh signalling pathway induces a previously undefined long non-coding RNA (Hilnc, Hedgehog signalling-induced long non-coding RNA), which controls hepatic lipid metabolism. Mutation of the Gli-binding sites in the Hilnc promoter region (HilncBM/BM) decreases the expression of Hilnc in vitro and in vivo. HilncBM/BM and Hilnc-knockout mice are resistant to diet-induced obesity and hepatic steatosis through attenuation of the peroxisome proliferator-activated receptor signalling pathway, as Hilnc directly interacts with IGF2BP2 to enhance Pparγ mRNA stability. Furthermore, we identify a potential functional human homologue of Hilnc, h-Hilnc, which has a similar function in regulating cellular lipid metabolism. These findings uncover a critical role of the Hh-Hilnc–IGF2BP2 signalling axis in lipid metabolism and suggest a potential therapeutic target for the treatment of diet-induced hepatic steatosis.",

author = "Yiao Jiang and Jiayin Peng and Jiawen Song and Juan He and Man Jiang and Jia Wang and Liya Ma and Yuang Wang and Moubin Lin and Hailong Wu and Zhao Zhang and Dong Gao and Yun Zhao",

note = "Funding Information: We thank the animal facility for animal husbandry, and technical supports from Core Facility for Cell Biology and the Genome Tagging Project Center, at CEMC. We acknowledge W. Yang for the providing reagents and helpful comments. This study was supported by grants from the National Key Research and Development Program of China (2020YFA0509000 and 2017YFA0503600 to Y.Z. and 2017YFA0505500 to D.G.), the National Natural Science Foundation of China (32130025 and 31630047 to Y.Z., 81772723 and 81830054 to D.G., 81874201 to M.B.L. and 31801184 to J.Y.P.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020905 to D.G.), the Basic Frontier Science Research Program of the Chinese Academy of Sciences (ZDBS-LY-SM015 to D.G.), the CAS-VPST Silk Road Science Fund 2019 (GJHZ201968 to D.G.) and the Science and Technology Commission of Shanghai Municipality (20Y11908300 to M.B.L.). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = nov,

doi = "10.1038/s42255-021-00488-3",

language = "English (US)",

volume = "3",

pages = "1569--1584",

journal = "Nature Metabolism",

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TY - JOUR

T1 - Loss of Hilnc prevents diet-induced hepatic steatosis through binding of IGF2BP2

AU - Jiang, Yiao

AU - Peng, Jiayin

AU - Song, Jiawen

AU - He, Juan

AU - Jiang, Man

AU - Wang, Jia

AU - Ma, Liya

AU - Wang, Yuang

AU - Lin, Moubin

AU - Wu, Hailong

AU - Zhang, Zhao

AU - Gao, Dong

AU - Zhao, Yun

N1 - Funding Information: We thank the animal facility for animal husbandry, and technical supports from Core Facility for Cell Biology and the Genome Tagging Project Center, at CEMC. We acknowledge W. Yang for the providing reagents and helpful comments. This study was supported by grants from the National Key Research and Development Program of China (2020YFA0509000 and 2017YFA0503600 to Y.Z. and 2017YFA0505500 to D.G.), the National Natural Science Foundation of China (32130025 and 31630047 to Y.Z., 81772723 and 81830054 to D.G., 81874201 to M.B.L. and 31801184 to J.Y.P.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020905 to D.G.), the Basic Frontier Science Research Program of the Chinese Academy of Sciences (ZDBS-LY-SM015 to D.G.), the CAS-VPST Silk Road Science Fund 2019 (GJHZ201968 to D.G.) and the Science and Technology Commission of Shanghai Municipality (20Y11908300 to M.B.L.). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021/11

Y1 - 2021/11

N2 - The Hedgehog (Hh) signalling pathway plays a critical role in regulating liver lipid metabolism and related diseases. However, the underlying mechanisms are poorly understood. Here, we show that the Hh signalling pathway induces a previously undefined long non-coding RNA (Hilnc, Hedgehog signalling-induced long non-coding RNA), which controls hepatic lipid metabolism. Mutation of the Gli-binding sites in the Hilnc promoter region (HilncBM/BM) decreases the expression of Hilnc in vitro and in vivo. HilncBM/BM and Hilnc-knockout mice are resistant to diet-induced obesity and hepatic steatosis through attenuation of the peroxisome proliferator-activated receptor signalling pathway, as Hilnc directly interacts with IGF2BP2 to enhance Pparγ mRNA stability. Furthermore, we identify a potential functional human homologue of Hilnc, h-Hilnc, which has a similar function in regulating cellular lipid metabolism. These findings uncover a critical role of the Hh-Hilnc–IGF2BP2 signalling axis in lipid metabolism and suggest a potential therapeutic target for the treatment of diet-induced hepatic steatosis.

AB - The Hedgehog (Hh) signalling pathway plays a critical role in regulating liver lipid metabolism and related diseases. However, the underlying mechanisms are poorly understood. Here, we show that the Hh signalling pathway induces a previously undefined long non-coding RNA (Hilnc, Hedgehog signalling-induced long non-coding RNA), which controls hepatic lipid metabolism. Mutation of the Gli-binding sites in the Hilnc promoter region (HilncBM/BM) decreases the expression of Hilnc in vitro and in vivo. HilncBM/BM and Hilnc-knockout mice are resistant to diet-induced obesity and hepatic steatosis through attenuation of the peroxisome proliferator-activated receptor signalling pathway, as Hilnc directly interacts with IGF2BP2 to enhance Pparγ mRNA stability. Furthermore, we identify a potential functional human homologue of Hilnc, h-Hilnc, which has a similar function in regulating cellular lipid metabolism. These findings uncover a critical role of the Hh-Hilnc–IGF2BP2 signalling axis in lipid metabolism and suggest a potential therapeutic target for the treatment of diet-induced hepatic steatosis.

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U2 - 10.1038/s42255-021-00488-3

DO - 10.1038/s42255-021-00488-3

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SN - 2522-5812

VL - 3

SP - 1569

EP - 1584

JO - Nature Metabolism

JF - Nature Metabolism

IS - 11

ER -

Loss of Hilnc prevents diet-induced hepatic steatosis through binding of IGF2BP2

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