Palmitate Potentiates Lipopolysaccharide-Induced IL-6 Production via Coordinated Acetylation of H3K9/H3K18, p300, and RNA Polymerase II

Author:

Kochumon Shihab1,Jacob Texy1,Koshy Merin1,Al-Rashed Fatema1ORCID,Sindhu Sardar1ORCID,Al-Ozairi Ebaa2ORCID,Al-Mulla Fahd3ORCID,Rosen Evan D.45ORCID,Ahmad Rasheed1ORCID

Affiliation:

1. *Immunology and Microbiology Department, Dasman Diabetes Institute, Kuwait City, Kuwait;

2. †Medical Division, Dasman Diabetes Institute, Kuwait City, Kuwait;

3. ‡Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait;

4. §Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA; and

5. ¶Harvard Medical School, Boston, MA

Abstract

Abstract IL-6 is elevated in obese individuals and participates in the metabolic dysfunction associated with that condition. However, the mechanisms that promote IL-6 expression in obesity are incompletely understood. Because elevated levels of palmitate and LPS have been reported in obesity, we investigated whether these agents interact to potentiate IL-6 production. In this study, we report that LPS induces higher levels of IL-6 in human monocytes in the presence of palmitate. Notably, the priming effect of palmitate is associated with enhanced p300 binding and transcription factor recruitment to Il6 promoter regions. Gene silencing of p300 blocks this action of palmitate. RNA polymerase II recruitment was also enhanced at the Il6 promoter in palmitate/LPS-exposed cells. Acetylation levels of H3K9 and H3K18 were increased in monocytes treated with palmitate. Moreover, LPS stimulation of palmitate-treated cells led to increased levels of the transcriptionally permissive acetylation marks H3K9/H3K18 in the Il6 promoter compared with LPS alone. The effect of palmitate on LPS-induced IL-6 production was suppressed by the inhibition of histone acetyltransferases. Conversely, histone deacetylase inhibitors trichostatin A or sodium butyrate can substitute for palmitate in IL-6 production. Esterification of palmitate with CoA was involved, whereas β-oxidation and ceramide biosynthesis were not required, for the induction of IL-6 and H3K9/H3K18 acetylation. Monocytes of obese individuals showed significantly higher H3K9/H3K18 acetylation and Il6 expression. Overall, our findings support a model in which increased levels of palmitate in obesity create a setting for LPS to potentiate IL-6 production via chromatin remodeling, enabling palmitate to contribute to metabolic inflammation.

Funder

Kuwait Foundation for the Advancement of Sciences

Foundation for the National Institutes of Health

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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