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 citas
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- Universidad u hospital
- Duke-NUS Medical School
- Universidad u hospital
- Louisiana Clinical and Translational Science Center
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- National Institutes of Health
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- Medical Research Council
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- National Medical Research Council
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- National Heart, Lung, and Blood Institute
- Gobierno
- National Institute of General Medical Sciences
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- NHLBI NIH HHS
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- NIGMS NIH HHS
- Subvenciones
- 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)
Según 9 financiadores declarados y la declaración de financiación del texto completo.
Publicación
- Publicado
- 2024-07-19 · Mol Metab · vol. 87 · pág. 101997
- Editorial
- Elsevier BV
- Citado
- 8 citas · más que el 88% de estudios similares · 2.1× el promedio de su campo
- Referencias
- 73 trabajos
- Acceso
- Acceso abierto (revista) · CC-BY-NC
- Áreas de investigación
- Liver Disease Diagnosis and Treatment · Autophagy in Disease and Therapy · Diet and metabolism studies
- Palabras clave
- 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 autores
- Madhulika Tripathi🇸🇬National University of Singapore
- Karine Cécile Gauthier🇫🇷Lyon 1 Université; École Normale Supérieure de Lyon; Centre National de la Recherche Scientifique; Institut de Génomique Fonctionnelle de Lyon
- Reddemma Sandireddy🇸🇬National University of Singapore
- Jin Zhou🇸🇬National University of Singapore
- Priyanka Guptta🇸🇬National University of Singapore
- Suganya Sakthivel🇸🇬National University of Singapore
- Wei Wen Teo🇸🇬National University of Singapore
- Yadanar Than Naing🇸🇬National University of Singapore
- Kabilesh Arul🇸🇬National University of Singapore
- Keziah Tikno🇸🇬National University of Singapore
- Sung‐Hee Park🇺🇸Duke University
- Yajun Wu
- Lijin Wang🇺🇸🇸🇬Pennington Biomedical Research Center; National University of Singapore; Duke-NUS Medical School
- Boon‐Huat Bay
- Lei Sun🇸🇬National University of Singapore
- Vincent Giguère🇨🇦McGill University
- Pierce K. H. Chow🇸🇬Singapore General Hospital; National Cancer Centre Singapore
- Sujoy Ghosh🇺🇸🇸🇬Pennington Biomedical Research Center; National University of Singapore; Duke-NUS Medical School
- Donald Patrick McDonnell🇺🇸Duke University
- Paul M. Yen🇸🇬🇺🇸National University of Singapore; Duke University; Duke-NUS Medical School
- Brijesh Kumar Singh🇸🇬Duke-NUS Medical School
Resumen
El texto original del estudio, en el idioma en que se publicó.
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.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial (CC BY-NC).
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