The RNA binding protein HuR is a gatekeeper of liver homeostasis

Pallavi Subramanian; Sofia Gargani; Alessandra Palladini; Margarita Chatzimike; Michal Grzybek; Mirko Peitzsch; Anastasios D Papanastasiou; Iryna Pyrina; Vasileios Ntafis; Bettina Gercken; Mathias Lesche; Andreas Petzold; Anupam Sinha; Marina Nati; Veera Raghavan Thangapandi; Ioannis Kourtzelis; Margarita Andreadou; Anke Witt; Andreas Dahl; Ralph Burkhardt; Robert Haase; António Miguel de Jesus Domingues; Ian Henry; Nicola Zamboni; Peter Mirtschink; Kyoung-Jin Chung; Jochen Hampe; Ünal Coskun; Dimitris L Kontoyiannis; Triantafyllos Chavakis

doi:10.1002/hep.32153

The RNA binding protein HuR is a gatekeeper of liver homeostasis

Pallavi Subramanian, Sofia Gargani, Alessandra Palladini, Margarita Chatzimike, Michal Grzybek, Mirko Peitzsch, Anastasios D Papanastasiou, Iryna Pyrina, Vasileios Ntafis, Bettina Gercken, Mathias Lesche, Andreas Petzold, Anupam Sinha, Marina Nati, Veera Raghavan Thangapandi, Ioannis Kourtzelis, Margarita Andreadou, Anke Witt, Andreas Dahl, Ralph BurkhardtRobert Haase, António Miguel de Jesus Domingues, Ian Henry, Nicola Zamboni, Peter Mirtschink, Kyoung-Jin Chung, Jochen Hampe, Ünal Coskun, Dimitris L Kontoyiannis, Triantafyllos Chavakis

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is initiated by steatosis and can progress via fibrosis and cirrhosis to hepatocellular carcinoma (HCC). The RNA binding protein HuR controls RNAs at the posttranscriptional level; hepatocyte HuR has been implicated in the regulation of diet-induced hepatic steatosis. The present study aimed to understand the role of hepatocyte-HuR in NAFLD development and progression to fibrosis and HCC.

APPROACH AND RESULTS: Hepatocyte-specific HuR-deficient mice and control HuR-sufficient mice were fed either a normal diet or a NAFLD-inducing diet. Hepatic lipid accumulation, inflammation, fibrosis and HCC development were studied by histology, flow cytometry, quantitative PCR and RNA sequencing. The liver lipidome was characterized by lipidomics analysis and the HuR-RNA interactions in the liver were mapped by RNA immunoprecipitation-sequencing. Hepatocyte-specific HuR-deficient mice displayed spontaneous hepatic steatosis and fibrosis predisposition, compared to control HuR-sufficient mice. On a NAFLD-inducing diet, hepatocyte-specific HuR-deficiency resulted in exacerbated inflammation, fibrosis and HCC-like tumor development. A multi-omic approach, including lipidomics, transcriptomics and RNA-immunoprecipitation sequencing revealed that HuR orchestrates a protective network of hepatic-metabolic and lipid homeostasis-maintaining pathways. Consistently, HuR-deficient livers accumulated, already at steady-state, a triglyceride signature resembling that of NAFLD livers. Moreover, upregulation of Spp1 and its product osteopontin mediated, at least partially, the fibrosis development in hepatocyte-specific HuR deficiency on a NAFLD-inducing diet, as shown by experiments utilizing antibody blockade of osteopontin.

CONCLUSIONS: HuR is a gatekeeper of liver homeostasis preventing NAFLD-related fibrosis and HCC, suggesting that the HuR-dependent network could be exploited therapeutically.

Original language	English
Journal	Hepatology
DOIs	https://doi.org/10.1002/hep.32153
Publication status	E-pub ahead of print - 14 Sept 2021

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Subramanian, P., Gargani, S., Palladini, A., Chatzimike, M., Grzybek, M., Peitzsch, M., Papanastasiou, A. D., Pyrina, I., Ntafis, V., Gercken, B., Lesche, M., Petzold, A., Sinha, A., Nati, M., Thangapandi, V. R., Kourtzelis, I., Andreadou, M., Witt, A., Dahl, A., ... Chavakis, T. (2021). The RNA binding protein HuR is a gatekeeper of liver homeostasis. Hepatology. Advance online publication. https://doi.org/10.1002/hep.32153

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title = "The RNA binding protein HuR is a gatekeeper of liver homeostasis",

abstract = "BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is initiated by steatosis and can progress via fibrosis and cirrhosis to hepatocellular carcinoma (HCC). The RNA binding protein HuR controls RNAs at the posttranscriptional level; hepatocyte HuR has been implicated in the regulation of diet-induced hepatic steatosis. The present study aimed to understand the role of hepatocyte-HuR in NAFLD development and progression to fibrosis and HCC.APPROACH AND RESULTS: Hepatocyte-specific HuR-deficient mice and control HuR-sufficient mice were fed either a normal diet or a NAFLD-inducing diet. Hepatic lipid accumulation, inflammation, fibrosis and HCC development were studied by histology, flow cytometry, quantitative PCR and RNA sequencing. The liver lipidome was characterized by lipidomics analysis and the HuR-RNA interactions in the liver were mapped by RNA immunoprecipitation-sequencing. Hepatocyte-specific HuR-deficient mice displayed spontaneous hepatic steatosis and fibrosis predisposition, compared to control HuR-sufficient mice. On a NAFLD-inducing diet, hepatocyte-specific HuR-deficiency resulted in exacerbated inflammation, fibrosis and HCC-like tumor development. A multi-omic approach, including lipidomics, transcriptomics and RNA-immunoprecipitation sequencing revealed that HuR orchestrates a protective network of hepatic-metabolic and lipid homeostasis-maintaining pathways. Consistently, HuR-deficient livers accumulated, already at steady-state, a triglyceride signature resembling that of NAFLD livers. Moreover, upregulation of Spp1 and its product osteopontin mediated, at least partially, the fibrosis development in hepatocyte-specific HuR deficiency on a NAFLD-inducing diet, as shown by experiments utilizing antibody blockade of osteopontin.CONCLUSIONS: HuR is a gatekeeper of liver homeostasis preventing NAFLD-related fibrosis and HCC, suggesting that the HuR-dependent network could be exploited therapeutically.",

author = "Pallavi Subramanian and Sofia Gargani and Alessandra Palladini and Margarita Chatzimike and Michal Grzybek and Mirko Peitzsch and Papanastasiou, {Anastasios D} and Iryna Pyrina and Vasileios Ntafis and Bettina Gercken and Mathias Lesche and Andreas Petzold and Anupam Sinha and Marina Nati and Thangapandi, {Veera Raghavan} and Ioannis Kourtzelis and Margarita Andreadou and Anke Witt and Andreas Dahl and Ralph Burkhardt and Robert Haase and Domingues, {Ant{\'o}nio Miguel de Jesus} and Ian Henry and Nicola Zamboni and Peter Mirtschink and Kyoung-Jin Chung and Jochen Hampe and {\"U}nal Coskun and Kontoyiannis, {Dimitris L} and Triantafyllos Chavakis",

year = "2021",

month = sep,

day = "14",

doi = "10.1002/hep.32153",

language = "English",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Wiley-Blackwell",

}

Subramanian, P, Gargani, S, Palladini, A, Chatzimike, M, Grzybek, M, Peitzsch, M, Papanastasiou, AD, Pyrina, I, Ntafis, V, Gercken, B, Lesche, M, Petzold, A, Sinha, A, Nati, M, Thangapandi, VR, Kourtzelis, I, Andreadou, M, Witt, A, Dahl, A, Burkhardt, R, Haase, R, Domingues, AMDJ, Henry, I, Zamboni, N, Mirtschink, P, Chung, K-J, Hampe, J, Coskun, Ü, Kontoyiannis, DL & Chavakis, T 2021, 'The RNA binding protein HuR is a gatekeeper of liver homeostasis', Hepatology. https://doi.org/10.1002/hep.32153

TY - JOUR

T1 - The RNA binding protein HuR is a gatekeeper of liver homeostasis

AU - Subramanian, Pallavi

AU - Gargani, Sofia

AU - Palladini, Alessandra

AU - Chatzimike, Margarita

AU - Grzybek, Michal

AU - Peitzsch, Mirko

AU - Papanastasiou, Anastasios D

AU - Pyrina, Iryna

AU - Ntafis, Vasileios

AU - Gercken, Bettina

AU - Lesche, Mathias

AU - Petzold, Andreas

AU - Sinha, Anupam

AU - Nati, Marina

AU - Thangapandi, Veera Raghavan

AU - Kourtzelis, Ioannis

AU - Andreadou, Margarita

AU - Witt, Anke

AU - Dahl, Andreas

AU - Burkhardt, Ralph

AU - Haase, Robert

AU - Domingues, António Miguel de Jesus

AU - Henry, Ian

AU - Zamboni, Nicola

AU - Mirtschink, Peter

AU - Chung, Kyoung-Jin

AU - Hampe, Jochen

AU - Coskun, Ünal

AU - Kontoyiannis, Dimitris L

AU - Chavakis, Triantafyllos

PY - 2021/9/14

Y1 - 2021/9/14

N2 - BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is initiated by steatosis and can progress via fibrosis and cirrhosis to hepatocellular carcinoma (HCC). The RNA binding protein HuR controls RNAs at the posttranscriptional level; hepatocyte HuR has been implicated in the regulation of diet-induced hepatic steatosis. The present study aimed to understand the role of hepatocyte-HuR in NAFLD development and progression to fibrosis and HCC.APPROACH AND RESULTS: Hepatocyte-specific HuR-deficient mice and control HuR-sufficient mice were fed either a normal diet or a NAFLD-inducing diet. Hepatic lipid accumulation, inflammation, fibrosis and HCC development were studied by histology, flow cytometry, quantitative PCR and RNA sequencing. The liver lipidome was characterized by lipidomics analysis and the HuR-RNA interactions in the liver were mapped by RNA immunoprecipitation-sequencing. Hepatocyte-specific HuR-deficient mice displayed spontaneous hepatic steatosis and fibrosis predisposition, compared to control HuR-sufficient mice. On a NAFLD-inducing diet, hepatocyte-specific HuR-deficiency resulted in exacerbated inflammation, fibrosis and HCC-like tumor development. A multi-omic approach, including lipidomics, transcriptomics and RNA-immunoprecipitation sequencing revealed that HuR orchestrates a protective network of hepatic-metabolic and lipid homeostasis-maintaining pathways. Consistently, HuR-deficient livers accumulated, already at steady-state, a triglyceride signature resembling that of NAFLD livers. Moreover, upregulation of Spp1 and its product osteopontin mediated, at least partially, the fibrosis development in hepatocyte-specific HuR deficiency on a NAFLD-inducing diet, as shown by experiments utilizing antibody blockade of osteopontin.CONCLUSIONS: HuR is a gatekeeper of liver homeostasis preventing NAFLD-related fibrosis and HCC, suggesting that the HuR-dependent network could be exploited therapeutically.

AB - BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is initiated by steatosis and can progress via fibrosis and cirrhosis to hepatocellular carcinoma (HCC). The RNA binding protein HuR controls RNAs at the posttranscriptional level; hepatocyte HuR has been implicated in the regulation of diet-induced hepatic steatosis. The present study aimed to understand the role of hepatocyte-HuR in NAFLD development and progression to fibrosis and HCC.APPROACH AND RESULTS: Hepatocyte-specific HuR-deficient mice and control HuR-sufficient mice were fed either a normal diet or a NAFLD-inducing diet. Hepatic lipid accumulation, inflammation, fibrosis and HCC development were studied by histology, flow cytometry, quantitative PCR and RNA sequencing. The liver lipidome was characterized by lipidomics analysis and the HuR-RNA interactions in the liver were mapped by RNA immunoprecipitation-sequencing. Hepatocyte-specific HuR-deficient mice displayed spontaneous hepatic steatosis and fibrosis predisposition, compared to control HuR-sufficient mice. On a NAFLD-inducing diet, hepatocyte-specific HuR-deficiency resulted in exacerbated inflammation, fibrosis and HCC-like tumor development. A multi-omic approach, including lipidomics, transcriptomics and RNA-immunoprecipitation sequencing revealed that HuR orchestrates a protective network of hepatic-metabolic and lipid homeostasis-maintaining pathways. Consistently, HuR-deficient livers accumulated, already at steady-state, a triglyceride signature resembling that of NAFLD livers. Moreover, upregulation of Spp1 and its product osteopontin mediated, at least partially, the fibrosis development in hepatocyte-specific HuR deficiency on a NAFLD-inducing diet, as shown by experiments utilizing antibody blockade of osteopontin.CONCLUSIONS: HuR is a gatekeeper of liver homeostasis preventing NAFLD-related fibrosis and HCC, suggesting that the HuR-dependent network could be exploited therapeutically.

U2 - 10.1002/hep.32153

DO - 10.1002/hep.32153

M3 - Article

C2 - 34519101

SN - 0270-9139

JO - Hepatology

JF - Hepatology

ER -