Lipid deprivation amplifies type I IFN responses in monocytes through prenylation - insights from familial combined hypolipidemia type 2

Sep 28, 2026

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Familial Combined Hypolipidemia type 2 (FHBL2) is a genetic disorder caused by loss-of-function mutations in the ANGPTL3 gene, associated with hypolipidemia and protection from atherosclerotic cardiovascular disease. This work tests how immunometabolic events shape an atheroprotective immune phenotype. Monocytes from FHBL2 patients and controls were profiled in vivo/ex vivo by gene expression and phenotyping, while lipid-deprived cells were studied in vitro. FHBL2 leukocytes showed reduced intracellular lipids, a spontaneous type I IFN signature, and increased IFN sensitivity. Lipid restriction activated mevalonate/isoprenoid synthesis and prenylation, linking these changes to elevated IFN responsiveness and repression of IL-1β production, alongside suppressed mitochondrial metabolism.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Abstract

Introduction

Type I interferons and inflammasome pathways

Crosstalk between IFN and inflammasome signaling

Links between innate immunity and cholesterol metabolism

Pinzon Grimaldos et al. Journal of Translational Medicine (2026) 24:3 [https://doi.org/10.1186/s12967-025-07448-5](https://doi.org/10.1186/s12967-025-07448-5) Journal of Translational Medicine RESEARCH Open Access Lipid deprivation amplifies type I IFN responses in monocytes through prenylation: insights from familial combined hypolipidemia type 2 Alessandra Pinzon Grimaldos 1, Ilenia Pacella 1,5, Tiziano Giacomelli 1,6, Simone Bini 1, Alessia Di Costanzo 1, Ilenia Minicocci 1, Laura D’Erasmo 1, Giuseppe Pietropaolo2, Valerio Licursi3, Marcello Arca 1 and Silvia Piconese 1,4* Abstract Familial Combined Hypolipidemia (FHBL2) is a genetic disorder caused by loss-of-function mutations in the Angiopoietin-like 3 (ANGPTL3) gene. FHBL2 subjects exhibit hypolipidemia and protection from atherosclerotic cardiovascular diseases. Here, we explored the hypothesis that immunometabolic events contribute to this atheroprotective phenotype. To this aim, circulating monocytes from FHBL2 subjects and controls were profiled through gene expression and phenotypic analysis in vivo and ex vivo. In parallel, immune responses were analyzed in monocytes that were lipid-deprived in vitro. In FHBL2 subjects, leukocytes exhibited lower content of intracellular lipids, together with a spontaneous type I IFN signature in vivo and higher sensitivity to IFN stimulation ex vivo. Lipid restriction in vitro was sufficient to recapitulate the higher IFN sensitivity in monocytes, while activating the mevalonate and isoprenoid synthetic pathway. These two events were linked, since a prenylation inhibitor reverted the high IFN response under lipid deprivation. Finally, we found that lipid restriction repressed, ina prenylation-and IFN-dependent fashion, the production of the inflammatory and proatherogenic cytokine IL-1β, and suppressed mitochondrial metabolism, which is a known trigger for inflammasome activation. In summary, we uncovered a novel immunometabolic mechanism linking lipid deprivation in monocytes, isoprenoid synthesis, enhanced IFN response, and IL-1β control. This circuit may provide an immunometabolic basis for the protection from atherosclerotic diseases in hypolipidemic subjects. Keywords Immunometabolism, Cholesterol, Interferon signature, Isoprenoids *Correspondence: Silvia Piconese [silvia.piconese@uniroma1.it](silvia.piconese@uniroma1.it) Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/l](http://creativecommons.org/l)icenses/by/4.0/. Pinzon Grimaldos et al. Journal of Translational Medicine (2026) 24:3 Page 2 of 16 Graphical Abstract Introduction Innate immune responses converge into two major pathways: the induction of type I interferons (IFNs) and the activation ofinflammasome. Detection of foreign or self-derived nucleic acids by specific sensors activates the transcription factors IRF3 and IRF7, which drive the expression of IFNα/β. Once secreted, these cytokines bind to the IFNAR1 receptor on neighboring cells, triggering phosphorylation of STAT1 and STAT2 and the formation of the ISGF3 complex. ISGF3 promotes the transcription of numerous

FAQs

What genetic cause defines familial combined hypolipidemia type 2 (FHBL2) in this study?

FHBL2 results from loss-of-function mutations in the ANGPTL3 gene.

How do FHBL2 subjects’ monocytes/leukocytes differ from controls regarding type I IFN responses?

They show lower intracellular lipid content, a spontaneous type I IFN signature in vivo, and higher sensitivity to IFN stimulation ex vivo.

What mechanism links lipid deprivation to stronger type I IFN responses?

Lipid restriction in vitro activates the mevalonate and isoprenoid synthetic pathway, and a prenylation inhibitor reverses the heightened IFN response.

Sep 28, 2026

Uploaded by acoobca