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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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Affiliated Author(s)
이재호송대규권택규임승순
Alternative Author(s)
Lee, Jae HoSong, Dae KyuKwon, Taeg KyuIm, Seung Soon
Journal Title
Mol Cell
ISSN
1097-2765
Issued Date
2021
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.
Department
Dept. of Anatomy (해부학)
Dept. of Physiology (생리학)
Dept. of Immunology (면역학)
Publisher
School of Medicine (의과대학)
Citation
Thuy T. P. Nguyen. (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
DOI
10.1016/j.molcel.2021.06.003
URI
http://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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