1139-P: CD36/FABP4/PPAR-d Axis-Induced Inflammation Is Dependent on ACSL1 under the Influence of Acute High-Fat Feeding

Abstract

Elevated levels of circulating inflammatory macrophages are associated with several metabolic syndrome (MetS) such as obesity and type II diabetes (T2D). The ingestion of high-fat meals was proven by several groups to act as a stimulus for systemic inflammatory responses via activation of peroxisome proliferator-activated receptors (PPARs). However, little is known about the lipid metabolism involved in macrophage-mediated inflammation under the influence of acute high fat feeding (AHFF). ACSL1 is a member of the long chain acyl-CoA synthetase (ACSL) family that plays key roles in fatty acid metabolism in various tissues. Our previous studies showed that attenuation of ACSL1 was sufficient to dampen inflammatory responses in macrophages challenged with TNF-α or LPS. In this study, we investigated the molecular mechanisms underlying AHFF-induced ACSL1 gene transcription in macrophages. In our work, we showed that four hours feeding of palmitic acid induced significant up-regulation of ACSL1 at both gene and protein levels. Both the inhibition and the deficiency of ACSL1, showed a significant impact on downregulating AHFF-induced inflammatory responses. Furthermore, the inhibition ACSL1 reduced mRNA levels of fatty acid uptake-related genes cluster of differentiation 36 (CD36) and fatty acid transport protein 4 (FATP4). However, inhibition of ACSL1 had no impact on lipogenesis related genes; SREBS, FAS and ACACA or fatty acid-oxidation genes; CPT-1a, CPT-1b and CPT2. Our data also showed that ACSL1 inhibition reduced PPARδ gene expression, while PPARα and PPARγ were not affected. Of note, macrophage intracellular lipid accumulation was attenuated during ACSL inhibition. Our findings suggest that targeting ACSL1 has a therapeutic potential to prevent AHFF-induced macrophage inflammation. Disclosure F. Alrashed: None. A. Al madhoun: None. S. T. Sindhu: None. A. Al-sayyar: None. F. Almulla: None. R. Ahmad: None. Funding Kuwait Foundation for the Advancement of Sciences (CB-2020-004)