MAPL loss dysregulates bile and liver metabolism in mice.
MUL1
PMP70
SUMO
hepatocellular carcinoma
peroxisome
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
06 Dec 2023
06 Dec 2023
Historique:
revised:
10
10
2023
received:
10
08
2023
accepted:
17
10
2023
medline:
11
12
2023
pubmed:
14
11
2023
entrez:
14
11
2023
Statut:
ppublish
Résumé
Mitochondrial and peroxisomal anchored protein ligase (MAPL) is a dual ubiquitin and small ubiquitin-like modifier (SUMO) ligase with roles in mitochondrial quality control, cell death and inflammation in cultured cells. Here, we show that MAPL function in the organismal context converges on metabolic control, as knockout mice are viable, insulin-sensitive, and protected from diet-induced obesity. MAPL loss leads to liver-specific activation of the integrated stress response, inducing secretion of stress hormone FGF21. MAPL knockout mice develop fully penetrant spontaneous hepatocellular carcinoma. Mechanistically, the peroxisomal bile acid transporter ABCD3 is a primary MAPL interacting partner and SUMOylated in a MAPL-dependent manner. MAPL knockout leads to increased bile acid production coupled with defective regulatory feedback in liver in vivo and in isolated primary hepatocytes, suggesting cell-autonomous function. Together, our findings establish MAPL function as a regulator of bile acid synthesis whose loss leads to the disruption of bile acid feedback mechanisms. The consequences of MAPL loss in liver, along with evidence of tumor suppression through regulation of cell survival pathways, ultimately lead to hepatocellular carcinogenesis.
Identifiants
pubmed: 37962001
doi: 10.15252/embr.202357972
pmc: PMC10702803
doi:
Substances chimiques
Mitochondrial Proteins
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Bile Acids and Salts
0
Ubiquitins
0
Banques de données
GEO
['GSE242501']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e57972Subventions
Organisme : Canada Research Chairs (Chaires de recherche du Canada)
Organisme : Canadian Cancer Society Research Institute
ID : 702139
Organisme : FRQ | Fonds de Recherche du Québec - Santé (FRQS)
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (IRSC)
ID : 68833
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (IRSC)
ID : 130340
Organisme : Sigrid Juséliuksen Säätiö (Sigrid Jusélius Stiftelse)
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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