Subramanian, Pallavi and Gargani, Sofia and Palladini, Alessandra and Chatzimike, Margarita and Grzybek, Michal and Peitzsch, Mirko and Papanastasiou, Anastasios D. and Pyrina, Iryna and Ntafis, Vasileios and Gercken, Bettina and Lesche, Mathias and Petzold, Andreas and Sinha, Anupam and Nati, Marina and Thangapandi, Veera Raghavan and Kourtzelis, Ioannis and Andreadou, Margarita and Witt, Anke and Dahl, Andreas and Burkhardt, Ralph and Haase, Robert and Domingues, Antonio Miguel de Jesus and Henry, Ian and Zamboni, Nicola and Mirtschink, Peter and Chung, Kyoung-Jin and Hampe, Jochen and Coskun, Unal and Kontoyiannis, Dimitris L. and Chavakis, Triantafyllos (2022) The RNA binding protein human antigen R is a gatekeeper of liver homeostasis. HEPATOLOGY, 75 (4). pp. 881-897. ISSN 0270-9139, 1527-3350
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NONALCOHOLIC STEATOHEPATITIS; SIGNALING PATHWAYS; INSULIN-RESISTANCE; HEPATIC STEATOSIS; BILE-ACIDS; ER STRESS; ACTIVATION; HUR; FXR; NAFLD; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Sep 2022 12:44 |
| Last Modified: | 27 Sep 2022 12:44 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48080 |
Actions (login required)
 |
View Item |
