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- Publisher Website: 10.1016/j.xcrm.2024.101477
- Scopus: eid_2-s2.0-85187987288
- PMID: 38508143
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Article: Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation
Title | Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation |
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Authors | |
Keywords | adenosine A1 receptor de novo lipogenesis inflammation MASH SCAP-SREBPs pathway |
Issue Date | 2024 |
Citation | Cell Reports Medicine, 2024, v. 5, n. 3, article no. 101477 How to Cite? |
Abstract | Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A1R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A1R in MAFLD remains unclear. Here, we report that liver-specific depletion of A1R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A1R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A1R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A1R agonists attenuate MAFL/MASH in an A1R-dependent manner. These results highlight that hepatic A1R is a potential target for MAFL/MASH therapy. |
Persistent Identifier | http://hdl.handle.net/10722/342689 |
DC Field | Value | Language |
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dc.contributor.author | Zhu, Weize | - |
dc.contributor.author | Hong, Ying | - |
dc.contributor.author | Tong, Zhaowei | - |
dc.contributor.author | He, Xiaofang | - |
dc.contributor.author | Li, Yan | - |
dc.contributor.author | Wang, Hao | - |
dc.contributor.author | Gao, Xinxin | - |
dc.contributor.author | Song, Pengtao | - |
dc.contributor.author | Zhang, Xianshan | - |
dc.contributor.author | Wu, Xiaochang | - |
dc.contributor.author | Tan, Zhenhua | - |
dc.contributor.author | Huang, Wenjin | - |
dc.contributor.author | Liu, Zekun | - |
dc.contributor.author | Bao, Yiyang | - |
dc.contributor.author | Ma, Junli | - |
dc.contributor.author | Zheng, Ningning | - |
dc.contributor.author | Xie, Cen | - |
dc.contributor.author | Ke, Xisong | - |
dc.contributor.author | Zhou, Wen | - |
dc.contributor.author | Jia, Wei | - |
dc.contributor.author | Li, Mingxiao | - |
dc.contributor.author | Zhong, Jing | - |
dc.contributor.author | Sheng, Lili | - |
dc.contributor.author | Li, Houkai | - |
dc.date.accessioned | 2024-04-17T07:05:33Z | - |
dc.date.available | 2024-04-17T07:05:33Z | - |
dc.date.issued | 2024 | - |
dc.identifier.citation | Cell Reports Medicine, 2024, v. 5, n. 3, article no. 101477 | - |
dc.identifier.uri | http://hdl.handle.net/10722/342689 | - |
dc.description.abstract | Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A1R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A1R in MAFLD remains unclear. Here, we report that liver-specific depletion of A1R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A1R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A1R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A1R agonists attenuate MAFL/MASH in an A1R-dependent manner. These results highlight that hepatic A1R is a potential target for MAFL/MASH therapy. | - |
dc.language | eng | - |
dc.relation.ispartof | Cell Reports Medicine | - |
dc.subject | adenosine A1 receptor | - |
dc.subject | de novo lipogenesis | - |
dc.subject | inflammation | - |
dc.subject | MASH | - |
dc.subject | SCAP-SREBPs pathway | - |
dc.title | Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1016/j.xcrm.2024.101477 | - |
dc.identifier.pmid | 38508143 | - |
dc.identifier.scopus | eid_2-s2.0-85187987288 | - |
dc.identifier.volume | 5 | - |
dc.identifier.issue | 3 | - |
dc.identifier.spage | article no. 101477 | - |
dc.identifier.epage | article no. 101477 | - |
dc.identifier.eissn | 2666-3791 | - |