The RNA binding protein human antigen R is a gatekeeper of liver homeostasis

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

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.

Details

Original languageEnglish
Pages (from-to)881-897
Number of pages17
JournalHepatology
Volume75
Issue number4
Publication statusPublished - 14 Sep 2021
Peer-reviewedYes

External IDs

PubMed 34519101

Keywords

DFG Classification of Subject Areas according to Review Boards

Subject groups, research areas, subject areas according to Destatis

ASJC Scopus subject areas

Keywords

  • Animals, Carcinoma, Hepatocellular/pathology, ELAV-Like Protein 1/metabolism, Homeostasis, Inflammation/metabolism, Liver/pathology, Liver Cirrhosis/metabolism, Liver Neoplasms/pathology, Mice, Mice, Inbred C57BL, Non-alcoholic Fatty Liver Disease/pathology, RNA, Triglycerides/metabolism

Library keywords