ACSL1 is a key regulator of inflammatory and macrophage foaming induced by short-term palmitate exposure or acute high-fat feeding

Fatema Al-Rashed; Dania Haddad; Ashraf Al Madhoun; Sardar Sindhu; Texy Jacob; Shihab Kochumon; Lina M Obeid; Fahd Al-Mulla; Yusuf A Hannun; Rasheed Ahmad

doi:10.1016/j.isci.2023.107145

ACSL1 is a key regulator of inflammatory and macrophage foaming induced by short-term palmitate exposure or acute high-fat feeding

iScience. 2023 Jun 15;26(7):107145. doi: 10.1016/j.isci.2023.107145. eCollection 2023 Jul 21.

Authors

Fatema Al-Rashed¹, Dania Haddad², Ashraf Al Madhoun^{2

3}, Sardar Sindhu^{1

3}, Texy Jacob¹, Shihab Kochumon¹, Lina M Obeid⁴, Fahd Al-Mulla², Yusuf A Hannun⁴, Rasheed Ahmad¹

Affiliations

¹ Immunology & Microbiology Department, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait.
² Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait.
³ Animal and Imaging Core Facilities, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait.
⁴ Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.

Abstract

Foamy and inflammatory macrophages play pathogenic roles in metabolic disorders. However, the mechanisms that promote foamy and inflammatory macrophage phenotypes under acute-high-fat feeding (AHFF) remain elusive. Herein, we investigated the role of acyl-CoA synthetase-1 (ACSL1) in favoring the foamy/inflammatory phenotype of monocytes/macrophages upon short-term exposure to palmitate or AHFF. Palmitate exposure induced a foamy/inflammatory phenotype in macrophages which was associated with increased ACSL1 expression. Inhibition/knockdown of ACSL1 in macrophages suppressed the foamy/inflammatory phenotype through the inhibition of the CD36-FABP4-p38-PPARδ signaling axis. ACSL1 inhibition/knockdown suppressed macrophage foaming/inflammation after palmitate stimulation by downregulating the FABP4 expression. Similar results were obtained using primary human monocytes. As expected, oral administration of ACSL1 inhibitor triacsin-C in mice before AHFF normalized the inflammatory/foamy phenotype of the circulatory monocytes by suppressing FABP4 expression. Our results reveal that targeting ACSL1 leads to the attenuation of the CD36-FABP4-p38-PPARδ signaling axis, providing a therapeutic strategy to prevent the AHFF-induced macrophage foaming and inflammation.

Keywords: Cellular physiology; Immunology; Physiology.

Grants and funding

R01 CA218678/CA/NCI NIH HHS/United States