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Meléndez-Rodríguez FAuthorTorres-Capelli MAuthorAragones JAuthor

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June 22, 2020
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Hypoxia-inducible factor 2α drives hepatosteatosis through the fatty acid translocase CD36

Publicated to:LIVER INTERNATIONAL. 40 (10): 2553-2567 - 2020-10-01 40(10), DOI: 10.1111/liv.14519

Authors: Rey E; Meléndez-Rodríguez F; Marañón P; Gil-Valle M; Carrasco AG; Torres-Capelli M; Chávez S; del Pozo-Maroto E; Rodríguez de Cía J; Aragonés J; García-Monzón C; González-Rodríguez Á

Affiliations

Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) - Author
Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas - Author
Hospital Universitario Santa Cristina - Author
Universidad Rey Juan Carlos - Author

Abstract

© 2020 The Authors. Liver International published by John Wiley & Sons Ltd Background & Aims: Molecular mechanisms by which hypoxia might contribute to hepatosteatosis, the earliest stage in non-alcoholic fatty liver disease (NAFLD) pathogenesis, remain still to be elucidated. We aimed to assess the impact of hypoxia-inducible factor 2α (HIF2α) on the fatty acid translocase CD36 expression and function in vivo and in vitro. Methods: CD36 expression and intracellular lipid content were determined in hypoxic hepatocytes, and in hypoxic CD36- or HIF2α -silenced human liver cells. Histological analysis, and HIF2α and CD36 expression were evaluated in livers from animals in which von Hippel-Lindau (Vhl) gene is inactivated (Vhlf/f-deficient mice), or both Vhl and Hif2a are simultaneously inactivated (Vhlf/fHif2α/f-deficient mice), and from 33 biopsy-proven NAFLD patients and 18 subjects with histologically normal liver. Results: In hypoxic hepatocytes, CD36 expression and intracellular lipid content were augmented. Noteworthy, CD36 knockdown significantly reduced lipid accumulation, and HIF2A gene silencing markedly reverted both hypoxia-induced events in hypoxic liver cells. Moreover livers from Vhlf/f-deficient mice showed histologic characteristics of non-alcoholic steatohepatitis (NASH) and increased CD36 mRNA and protein amounts, whereas both significantly decreased and NASH features markedly ameliorated in Vhlf/fHif2αf/f-deficient mice. In addition, both HIF2α and CD36 were significantly overexpressed within the liver of NAFLD patients and, interestingly, a significant positive correlation between hepatic transcript levels of CD36 and erythropoietin (EPO), a HIF2α -dependent gene target, was observed in NAFLD patients. Conclusions: This study provides evidence that HIF2α drives lipid accumulation in human hepatocytes by upregulating CD36 expression and function, and could contribute to hepatosteatosis setup.

Keywords

cd36hif2?hif2αhypoxianafldActivationCd36ContributesExpressionHif2 alphaHif2αHypoxiaLipid-metabolismLiver-diseaseMechanismsNafldObesityProteinSteatosis

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal LIVER INTERNATIONAL due to its progression and the good impact it has achieved in recent years, according to the agency Scopus (SJR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position , thus managing to position itself as a Q1 (Primer Cuartil), in the category Hepatology.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.16. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 1.42 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 9.95 (source consulted: Dimensions Sep 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-09-21, the following number of citations:

  • WoS: 19
  • Scopus: 31
  • Europe PMC: 17

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-09-21:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 35.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 35 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 2.
  • The number of mentions on the social network X (formerly Twitter): 3 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
  • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://repositorio.uam.es/handle/10486/694886