The RNA binding protein human antigen R is a gatekeeper of liver homeostasis
Year: 2021
Type: article
Abstract: BACKGROUND AND AIMS: NAFLD is initiated by steatosis and can progress through fibrosis and cirrhosis to HCC. The RNA binding protein human antigen R (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 an 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 an 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, up-regulation of secreted phosphoprotein 1 expression mediated, at least partially, fibrosis development in hepatocyte-specific HuR deficiency on an NAFLD-inducing diet, as shown by experiments using 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.
Source: Hepatology
DOI: 10.1002/hep.32153
Authors: 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
Institutions: Technische Universität Dresden, Alexander Fleming Biomedical Sciences Research Center, Helmholtz Munich, German Center for Diabetes Research, Paul Langerhans Institute Dresden, University of West Attica, DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering, German Cancer Research Center, Nationales Centrum für Tumorerkrankungen Dresden, German Cancer Research Center (DKFZ) Dresden, University of York, Hull York Medical School, University Hospital Regensburg, Max Planck Institute of Molecular Cell Biology and Genetics, ETH Zurich, Institute for Molecular Systems Biology, Aristotle University of Thessaloniki
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $1,165
OpenAlex ID: W3201301137