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SREBP-1c impairs ULK1 sulfhydration-mediated autophagic flux to promote hepatic steatosis in high-fat-diet-fed mice

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Author(s)
Thuy T. P. NguyenDo-Young KimYu-Geon LeeYoung-Seung LeeXuan T TruongJae-Ho LeeDae-Kyu SongTaeg Kyu KwonSo-Hyun ParkChang Hwa JungChangjong MoonTimothy F. OsborneSeung-Soon ImTae-Il Jeon
Keimyung Author(s)
Lee, Jae HoSong, Dae KyuKwon, Taeg KyuIm, Seung Soon
Department
Dept. of Anatomy (해부학)
Dept. of Physiology (생리학)
Dept. of Immunology (면역학)
Journal Title
Mol Cell
Issued Date
2021
Volume
81
Issue
18
Keyword
autophagyhydrogen sulfideSREBP-1csteatosissulfhydrationULK1
Abstract
A metabolic imbalance between lipid synthesis and degradation can lead to hepatic lipid accumulation, a characteristic of patients with non-alcoholic fatty liver disease (NAFLD). Here, we report that high-fat-diet-induced sterol regulatory element-binding protein (SREBP)-1c, a key transcription factor that regulates lipid biosynthesis, impairs autophagic lipid catabolism via altered H2S signaling. SREBP-1c reduced cystathionine gamma-lyase (CSE) via miR-216a, which in turn decreased hepatic H2S levels and sulfhydration-dependent activation of Unc-51-like autophagy-activating kinase 1 (ULK1). Furthermore, Cys951Ser mutation of ULK1 decreased autolysosome formation and promoted hepatic lipid accumulation in mice, suggesting that the loss of ULK1 sulfhydration was directly associated with the pathogenesis of NAFLD. Moreover, silencing of CSE in SREBP-1c knockout mice increased liver triglycerides, confirming the connection between CSE, autophagy, and SREBP-1c. Overall, our results uncover a 2-fold mechanism for SREBP-1c-driven hepatic lipid accumulation through reciprocal activation and inhibition of hepatic lipid biosynthesis and degradation, respectively.
Keimyung Author(s)(Kor)
이재호
송대규
권택규
임승순
Publisher
School of Medicine (의과대학)
Citation
Thuy T. P. Nguyen et al. (2021). SREBP-1c impairs ULK1 sulfhydration-mediated autophagic flux to promote hepatic steatosis in high-fat-diet-fed mice. Mol Cell, 81(18), 3820–3832. doi: 10.1016/j.molcel.2021.06.003
Type
Article
ISSN
1097-2765
Source
https://www.sciencedirect.com/science/article/abs/pii/S1097276521004500
DOI
10.1016/j.molcel.2021.06.003
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/43975
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Anatomy (해부학)
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
1. School of Medicine (의과대학) > Dept. of Physiology (생리학)
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