Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
Cell reports. Medicine - 5(2024), 3 vom: 19. März, Seite 101477 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhu, Weize [VerfasserIn] |
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| Links: |
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| Themen: |
Adenosine A1 receptor |
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| Anmerkungen: |
Date Completed 22.03.2024 Date Revised 03.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1016/j.xcrm.2024.101477 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369977270 |
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| 245 | 1 | 0 | |a Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation |
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| 520 | |a Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a MASH | |
| 650 | 4 | |a SCAP-SREBPs pathway | |
| 650 | 4 | |a adenosine A1 receptor | |
| 650 | 4 | |a de novo lipogenesis | |
| 650 | 4 | |a inflammation | |
| 650 | 7 | |a Receptor, Adenosine A1 |2 NLM | |
| 700 | 1 | |a Hong, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Tong, Zhaowei |e verfasserin |4 aut | |
| 700 | 1 | |a He, Xiaofang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Xinxin |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Pengtao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xianshan |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiaochang |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Zhenhua |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Wenjin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zekun |e verfasserin |4 aut | |
| 700 | 1 | |a Bao, Yiyang |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Junli |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Ningning |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Cen |e verfasserin |4 aut | |
| 700 | 1 | |a Ke, Xisong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Mingxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Sheng, Lili |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Houkai |e verfasserin |4 aut | |
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