Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting
Tripathi M, Gauthier K, Sandireddy R, Zhou J, Guptta P, Sakthivel S, Teo WW, Naing YT, Arul K, Tikno K, Park SH, Wu Y, Wang L, Bay BH, Sun L, Giguere V, Chow PKH, Ghosh S, McDonnell DP, Yen PM, Singh BK
Molecular metabolism · 7 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Mechanisms only
Who paid for it
- Funding
- Independent funding
- University or hospital
- Duke-NUS Medical School
- University or hospital
- Louisiana Clinical and Translational Science Center
- Government
- National Institutes of Health
- Government
- Medical Research Council
- Government
- National Medical Research Council
- Government
- National Heart, Lung, and Blood Institute
- Government
- National Institute of General Medical Sciences
- Government
- NHLBI NIH HHS
- Government
- NIGMS NIH HHS
- Grants
- National Institute of General Medical Sciences (2 U54-GM104940); National Heart, Lung, and Blood Institute (R01 HL146462); National Heart, Lung, and Blood Institute (NHLBI R01HL146462-01); National Medical Research Council (MOH-OFIRG19may0002); Louisiana Clinical and Translational Science Center (NIGMS 2U54GM104940); National Medical Research Council (NMRC/OFYIRG/0002/2016)
Based on 9 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2024-07-19 · Mol Metab · vol. 87 · p. 101997
- Publisher
- Elsevier BV
- Cited
- 8 citations · more than 88% of similar papers · 2.1× the field average
- References
- 73 works
- Access
- Open access (journal) · CC-BY-NC
- Research areas
- Liver Disease Diagnosis and Treatment · Autophagy in Disease and Therapy · Diet and metabolism studies
- Keywords
- Steatohepatitis, Translation (biology), Lysosome, Mechanism (biology), Nonalcoholic steatohepatitis, Medicine, Fatty liver, Endocrinology, Internal medicine, Biology, Biochemistry, Gene, Disease, Messenger RNA, Philosophy, Enzyme
- MeSH
- liver, lysosomes, hepatocytes, animals, mice, inbred c57bl, mice, knockout, humans, mice, phosphoproteins, ribosomal proteins, fasting, protein biosynthesis, autophagy, male, non-alcoholic fatty liver disease
21 authors
From SG, FR, US, CA
- Madhulika TripathiNational University of Singapore
- Karine Cécile GauthierLyon 1 Université; École Normale Supérieure de Lyon; Centre National de la Recherche Scientifique; Institut de Génomique Fonctionnelle de Lyon
- Reddemma SandireddyNational University of Singapore
- Jin ZhouNational University of Singapore
- Priyanka GupttaNational University of Singapore
- Suganya SakthivelNational University of Singapore
Abstract
Objective
Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH).
Methods
Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo.
Results
We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH.
Conclusions
Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY-NC).
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