{rfName}
My

Indexed in

License and use

Icono OpenAccess

Citations

192

Altmetrics

Grant support

This work was supported by grants SAF-2011-23031, SAF-2012-34831 from Plan Nacional de I+D, Spain, Fundacio Marato de TV3, La Mutua Madrilena, PI11/0325 (META) grant from the Instituto Salud Carlos III, and by the support of CIBEREHD; the center grant P50-AA-11999 Research Center for Liver and Pancretic Diseases funded by NIAAA/NIH. Laura Martinez acknowledges support from Formacion de Personal Investigador (FPI) fellowship BES-2009-027637, Boehringer Ingelheim and Journal of Cell Science Travel Fellowships.

Analysis of institutional authors

Torres Nuñez, SandraAuthorMartinez, LAuthorTorres, SAuthorCaballeria, JAuthorFernandez-Checa, JcAuthorGarcia-Ruiz, CCorresponding Author

Share

January 11, 2016
Publications
>
Article
Sí

Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis

Publicated to:Oncotarget. 6 (39): 41479-41496 - 2015-12-08 6(39), DOI: 10.18632/oncotarget.6286

Authors: Martinez, Laura; Torres, Sandra; Baulies, Anna; Alarcon-Vila, Cristina; Elena, Montserrat; Fabrias, Gemma; Casas, Josefina; Caballeria, Joan; Fernandez-Checa, Jose C.; Garcia-Ruiz, Carmen;

Affiliations

CIBERehd, Barcelona, Spain - Author
CSIC, Cell Death & Proliferat, Inst Biomed Res Barcelona IIBB, Barcelona, Spain - Author
CSIC, Res Unit BioAct Mol RUBAM, Dept Quim Organ Biol, Inst Invest Quim & Ambientals Barcelona, Barcelona, Spain - Author
IDIBAPS, Biomed Diag Ctr, Hosp Clin & Prov Barcelona, Barcelona, Spain - Author
IDIBAPS, Liver Unit, Hosp Clin & Prov Barcelona, Barcelona, Spain - Author
Univ So Calif, Keck Sch Med, Res Ctr ALPD, Los Angeles, CA 90033 USA - Author
See more

Abstract

Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic acid (MA), a free fatty acid highly abundant in copra/palmist oils, is a predictor of nonalcoholic steatohepatitis (NASH) and stimulates ceramide synthesis. Here we investigated the synergism between MA and PA in ceramide synthesis, ER stress, lipotoxicity and NASH. Unlike PA, MA is not lipotoxic but potentiated PA-mediated lipoapoptosis, ER stress, caspase-3 activation and cytochrome c release in primary mouse hepatocytes (PMH). Moreover, MA kinetically sustained PA-induced total ceramide content by stimulating dehydroceramide desaturase and switched the ceramide profile from decreased to increased ceramide 14:0/ceramide16:0, without changing medium and long-chain ceramide species. PMH were more sensitive to equimolar ceramide14:0/ceramide16:0 exposure, which mimics the outcome of PA plus MA treatment on ceramide homeostasis, than to either ceramide alone. Treatment with myriocin to inhibit ceramide synthesis and tauroursodeoxycholic acid to prevent ER stress ameliorated PA plus MA induced apoptosis, similar to the protection afforded by the antioxidant BHA, the pan-caspase inhibitor z-VAD-Fmk and JNK inhibition. Moreover, ruthenium red protected PMH against PA and MA-induced cell death. Recapitulating in vitro findings, mice fed a diet enriched in PA plus MA exhibited lipodystrophy, hepatosplenomegaly, increased liver ceramide content and cholesterol levels, ER stress, liver damage, inflammation and fibrosis compared to mice fed diets enriched in PA or MA alone. The deleterious effects of PA plus MA-enriched diet were largely prevented by in vivo myriocin treatment. These findings indicate a causal link between ceramide synthesis and ER stress in lipotoxicity, and imply that the consumption of diets enriched in MA and PA can cause NASH associated with lipodystrophy.

Keywords

cell-deathchain-lengthendoplasmic reticulumffahepatocyteinduced apoptosisinhibitionmouse modelnafldoxidative stresspathology sectionratserine palmitoyltransferasesphingolipidsCell-deathChain-lengthEndoplasmic reticulumFfaHepatocyteInduced apoptosisInhibitionMouse modelNafldNonalcoholic fatty liverOxidative stressPathology sectionRatSerine palmitoyltransferaseSphingolipidSphingolipids

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Oncotarget due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2015, it was in position 36/213, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology.

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: 1.57. 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: 1.39 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 14.23 (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-16, the following number of citations:

  • WoS: 62
  • Scopus: 52
  • Europe PMC: 45

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 2025-07-16:

  • 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: 97.
  • 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: 105 (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: 2.35.
  • 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.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Martinez Guino, Laura) and Last Author (García Ruiz, Carmen).

the author responsible for correspondence tasks has been García Ruiz, Carmen.