101. The RNA binding protein HuR is a gatekeeper of liver homeostasis
- Author
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Subramanian, Pallavi, Gargani, Sofia, Palladini, Alessandra, Chatzimike, Margarita, Grzybek, Michal, Peitzsch, Mirko, Papanastasiou, Anastasios D, Pyrina, Iryna, Ntafis, Vasileios, Gercken, Bettina, Lesche, Mathias, Petzold, Andreas, Sinha, Anupam, Nati, Marina, Thangapandi, Veera Raghavan, Kourtzelis, Ioannis, Andreadou, Margarita, Witt, Anke, Dahl, Andreas, Burkhardt, Ralph, Haase, Robert, Domingues, António Miguel de Jesus, Henry, Ian, Zamboni, Nicola, Mirtschink, Peter, Chung, Kyoung-Jin, Hampe, Jochen, Coskun, Ünal, Kontoyiannis, Dimitris L, and Chavakis, Triantafyllos
- Subjects
Elavl1 ,Fxr ,Hur ,Nafld ,Nash ,Rna-binding Protein ,Bile Acid ,Hepatocellular Carcinoma ,Lipid Metabolism ,Liver ,Steatosis ,Triglycerides ,digestive system diseases - 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.
- Published
- 2022