The RNA binding protein human antigen R is a gatekeeper of liver homeostasis.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
revised:
08
09
2021
received:
02
02
2021
accepted:
10
09
2021
pubmed:
15
9
2021
medline:
3
5
2022
entrez:
14
9
2021
Statut:
ppublish
Résumé
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. 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. HuR is a gatekeeper of liver homeostasis, preventing NAFLD-related fibrosis and HCC, suggesting that the HuR-dependent network could be exploited therapeutically.
Sections du résumé
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.
Identifiants
pubmed: 34519101
doi: 10.1002/hep.32153
pii: 01515467-202204000-00011
doi:
Substances chimiques
ELAV-Like Protein 1
0
Elavl1 protein, mouse
0
Triglycerides
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
881-897Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
Références
Musso G, Cassader M, Gambino R. Non‐alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat Rev Drug Discov. 2016;15:249–74.
Rui L. Energy metabolism in the liver. Compr Physiol. 2014;4:177–97.
Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10:656–65.
Schwabe RF, Tabas I, Pajvani UB. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology. 2020;158:1913–28.
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51.
Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118:829–38.
Benegiamo G, Mure LS, Erikson G, Le HD, Moriggi E, Brown SA, et al. The RNA‐binding protein NONO coordinates hepatic adaptation to feeding. Cell Metab. 2018;27:404–18.e407.
Laggai S, Kessler SM, Boettcher S, Lebrun V, Gemperlein K, Lederer E, et al. The IGF2 mRNA binding protein p62/IGF2BP2‐2 induces fatty acid elongation as a critical feature of steatosis. J Lipid Res. 2014;55:1087–97.
Doller A, Pfeilschifter J, Eberhardt W. Signalling pathways regulating nucleo‐cytoplasmic shuttling of the mRNA‐binding protein HuR. Cell Signal. 2008;20:2165–73.
Grammatikakis I, Abdelmohsen K, Gorospe M. Posttranslational control of HuR function. Wiley Interdiscip Rev RNA. 2017;8:e1372.
Lourou N, Gavriilidis M, Kontoyiannis DL. Lessons from studying the AU‐rich elements in chronic inflammation and autoimmunity. J Autoimmun. 2019;104:102334.
Woodhoo A, Iruarrizaga‐Lejarreta M, Beraza N, García‐Rodríguez JL, Embade N, Fernández‐Ramos D, et al. Human antigen R contributes to hepatic stellate cell activation and liver fibrosis. Hepatology. 2012;56:1870–82.
Ge J, Chang N, Zhao Z, Tian L, Duan X, Yang L, et al. Essential roles of RNA‐binding protein HuR in activation of hepatic stellate cells induced by transforming growth factor‐beta1. Sci Rep. 2016;6:22141.
Zhang Z, Zong C, Jiang M, Hu H, Cheng X, Ni J, et al. Hepatic HuR modulates lipid homeostasis in response to high‐fat diet. Nat Commun. 2020;11:3067.
Stefan N, Haring HU. The metabolically benign and malignant fatty liver. Diabetes. 2011;60:2011–7.
Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102:731–44.
Watanabe M, Houten SM, Wang LI, Moschetta A, Mangelsdorf DJ, Heyman RA, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP‐1c. J Clin Invest. 2004;113:1408–18.
Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile‐acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008;7:678–93.
Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51:771–84.
Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A, Riccardi L, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology. 2004;127:1497–512.
Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol–activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 2012;13:213–24.
Moeini A, Cornella H, Villanueva A. Emerging signaling pathways in hepatocellular carcinoma. Liver Cancer. 2012;1:83–93.
Kotta‐Loizou I, Giaginis C, Theocharis S. Clinical significance of HuR expression in human malignancy. Med Oncol. 2014;31:161.
Wolf M, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross‐talk with hepatocytes. Cancer Cell. 2014;26:549–64.
Hassan HM, Isovic M, Kolendowski B, Bauer‐Maison N, Onabote O, Cecchini M, et al. Loss of thymine DNA glycosylase causes dysregulation of bile acid homeostasis and hepatocellular carcinoma. Cell Rep. 2020;31:107475.
Bergman S, Graeme‐Cook F, Pitman MB. The usefulness of the reticulin stain in the differential diagnosis of liver nodules on fine‐needle aspiration biopsy cell block preparations. Mod Pathol. 1997;10:1258–64.
Gorden DL, Myers DS, Ivanova PT, Fahy E, Maurya MR, Gupta S, et al. Biomarkers of NAFLD progression: a lipidomics approach to an epidemic. J Lipid Res. 2015;56:722–36.
Alamri H, Patterson NH, Yang E, Zoroquiain P, Lazaris A, Chaurand P, et al. Mapping the triglyceride distribution in NAFLD human liver by MALDI imaging mass spectrometry reveals molecular differences in micro and macro steatosis. Anal Bioanal Chem. 2019;411:885–94.
Orešič M, Hyötyläinen T, Kotronen A, Gopalacharyulu P, Nygren H, Arola J, et al. Prediction of non‐alcoholic fatty‐liver disease and liver fat content by serum molecular lipids. Diabetologia. 2013;56:2266–74.
Sanders FWB, Acharjee A, Walker C, Marney L, Roberts LD, Imamura F, et al. Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption. Genome Biol. 2018;19:79.
Yang R‐X, Hu C‐X, Sun W‐L, Pan Q, Shen F, Yang Z, et al. Serum monounsaturated triacylglycerol predicts steatohepatitis in patients with non‐alcoholic fatty liver disease and chronic hepatitis B. Sci Rep. 2017;7:10517.
Hinman MN, Lou H. Diverse molecular functions of Hu proteins. Cell Mol Life Sci. 2008;65:3168–81.
Marquardt A, Al‐Dabet MM, Ghosh S, Kohli S, Manoharan J, ElWakiel A, et al. Farnesoid X receptor agonism protects against diabetic tubulopathy: potential add‐on therapy for diabetic nephropathy. J Am Soc Nephrol. 2017;28:3182–9.
Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3:543–53.
Rutkowski DT, Wu J, Back S‐H, Callaghan MU, Ferris SP, Iqbal J, et al. UPR pathways combine to prevent hepatic steatosis caused by ER stress‐mediated suppression of transcriptional master regulators. Dev Cell. 2008;15:829–40.
Zhu C, Kim KJ, Wang X, Bartolome A, Salomao M, Dongiovanni P, et al. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2018;10:eaat0344.
Bruha R, Vitek L, Smid V. Osteopontin—a potential biomarker of advanced liver disease. Ann Hepatol. 2020;19:344–52.
Srikantan S, Gorospe M. UneCLIPsing HuR nuclear function. Mol Cell. 2011;43:319–21.
Cho E‐J, Yoon J‐H, Kwak M‐S, Jang ES, Lee J‐H, Yu SJ, et al. Tauroursodeoxycholic acid attenuates progression of steatohepatitis in mice fed a methionine‐choline‐deficient diet. Dig Dis Sci. 2014;59:1461–74.
Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313:1137–40.
Yang J‐S, Kim JT, Jeon J, Park HS, Kang GH, Park KS, et al. Changes in hepatic gene expression upon oral administration of taurine‐conjugated ursodeoxycholic acid in ob/ob mice. PLoS ONE. 2010;5:e13858.
Singh AB, Dong B, Kraemer FB, Xu Y, Zhang Y, Liu J. Farnesoid X receptor activation by obeticholic acid elevates liver low‐density lipoprotein receptor expression by mRNA stabilization and reduces plasma low‐density lipoprotein cholesterol in mice. Arterioscler Thromb Vasc Biol. 2018;38:2448–59.
Wobser H, Dorn C, Weiss TS, Amann T, Bollheimer C, Büttner R, et al. Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells. Cell Res. 2009;19:996–1005.
Wang X, Cai B, Yang X, Sonubi OO, Zheng ZE, Ramakrishnan R, et al. Cholesterol stabilizes TAZ in hepatocytes to promote experimental non‐alcoholic steatohepatitis. Cell Metab. 2020;31:969–86.e967.
Wang X, Zheng ZE, Caviglia JM, Corey KE, Herfel TM, Cai B, et al. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab. 2016;24:848–62.
Cao C, Sun J, Zhang D, Guo X, Xie L, Li X, et al. The long intergenic noncoding RNA UFC1, a target of microRNA 34a, interacts with the mRNA stabilizing protein HuR to increase levels of beta‐catenin in HCC cells. Gastroenterology. 2015;148:415–26.e418.
Zhang LF, Lou JT, Lu MH, Gao C, Zhao S, Li B, et al. Suppression of miR‐199a maturation by HuR is crucial for hypoxia‐induced glycolytic switch in hepatocellular carcinoma. EMBO J. 2015;34:2671–85.
Zhu H, Berkova Z, Mathur R, Sehgal L, Khashab T, Tao R‐H, et al. HuR suppresses Fas expression and correlates with patient outcome in liver cancer. Mol Cancer Res. 2015;13:809–18.