PMID- 36054206 OWN - NLM STAT- MEDLINE DCOM- 20220908 LR - 20230422 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 17 IP - 9 DP - 2022 TI - Transcriptional regulation of Acsl1 by CHREBP and NF-kappa B in macrophages during hyperglycemia and inflammation. PG - e0272986 LID - 10.1371/journal.pone.0272986 [doi] LID - e0272986 AB - Acyl-CoA synthetase 1 (ACSL1) is an enzyme that converts fatty acids to acyl-CoA-derivatives for lipid catabolism and lipid synthesis in general and can provide substrates for the production of mediators of inflammation in monocytes and macrophages. Acsl1 expression is increased by hyperglycemia and inflammatory stimuli in monocytes and macrophages, and promotes the pro-atherosclerotic effects of diabetes in mice. Yet, surprisingly little is known about the mechanisms underlying Acsl1 transcriptional regulation. Here we demonstrate that the glucose-sensing transcription factor, Carbohydrate Response Element Binding Protein (CHREBP), is a regulator of the expression of Acsl1 mRNA by high glucose in mouse bone marrow-derived macrophages (BMDMs). In addition, we show that inflammatory stimulation of BMDMs with lipopolysaccharide (LPS) increases Acsl1 mRNA via the transcription factor, NF-kappa B. LPS treatment also increases ACSL1 protein abundance and localization to membranes where it can exert its activity. Using an Acsl1 reporter gene containing the promoter and an upstream regulatory region, which has multiple conserved CHREBP and NF-kappa B (p65/RELA) binding sites, we found increased Acsl1 promoter activity upon CHREBP and p65/RELA expression. We also show that CHREBP and p65/RELA occupy the Acsl1 promoter in BMDMs. In primary human monocytes cultured in high glucose versus normal glucose, ACSL1 mRNA expression was elevated by high glucose and further enhanced by LPS treatment. Our findings demonstrate that CHREBP and NF-kappa B control Acsl1 expression under hyperglycemic and inflammatory conditions. FAU - Thevkar-Nagesh, Prashanth AU - Thevkar-Nagesh P AD - Department of Microbiology, NYU School of Medicine, New York, NY, United States of America. AD - Department of Medicine, NYU School of Medicine, New York, NY, United States of America. AD - Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America. FAU - Habault, Justine AU - Habault J AUID- ORCID: 0000-0001-6375-6428 AD - Department of Microbiology, NYU School of Medicine, New York, NY, United States of America. FAU - Voisin, Maud AU - Voisin M AD - Department of Microbiology, NYU School of Medicine, New York, NY, United States of America. FAU - Ruff, Sophie E AU - Ruff SE AD - Department of Microbiology, NYU School of Medicine, New York, NY, United States of America. FAU - Ha, Susan AU - Ha S AD - Department of Urology, NYU School of Medicine, New York, NY, United States of America. FAU - Ruoff, Rachel AU - Ruoff R AD - Department of Microbiology, NYU School of Medicine, New York, NY, United States of America. FAU - Chen, Xi AU - Chen X AD - Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America. AD - Hosptial for Special Surgery, New York, NY, United States of America. FAU - Rawal, Shruti AU - Rawal S AD - Department of Medicine, NYU School of Medicine, New York, NY, United States of America. FAU - Zahr, Tarik AU - Zahr T AUID- ORCID: 0000-0002-2754-6092 AD - Department of Medicine, NYU School of Medicine, New York, NY, United States of America. FAU - Szabo, Gyongyi AU - Szabo G AUID- ORCID: 0000-0003-0836-2527 AD - Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America. FAU - Rogatsky, Inez AU - Rogatsky I AD - Hosptial for Special Surgery, New York, NY, United States of America. AD - Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School for Medical Sciences, New York, NY, United States of America. FAU - Fisher, Edward A AU - Fisher EA AD - Department of Microbiology, NYU School of Medicine, New York, NY, United States of America. AD - Department of Medicine, NYU School of Medicine, New York, NY, United States of America. FAU - Garabedian, Michael J AU - Garabedian MJ AUID- ORCID: 0000-0001-8915-7378 AD - Department of Microbiology, NYU School of Medicine, New York, NY, United States of America. LA - eng GR - R01 AA011576/AA/NIAAA NIH HHS/United States GR - R01 AI148129/AI/NIAID NIH HHS/United States GR - P01 HL131481/HL/NHLBI NIH HHS/United States GR - R21 NS110520/NS/NINDS NIH HHS/United States GR - R01 DK099087/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20220902 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors) RN - 0 (Lipopolysaccharides) RN - 0 (Mlxipl protein, mouse) RN - 0 (NF-kappa B) RN - 0 (NF-kappa B p50 Subunit) RN - 0 (RNA, Messenger) RN - 147257-52-1 (Nfkb1 protein, mouse) RN - EC 6.2.1.- (ACSL1 protein, mouse) RN - EC 6.2.1.- (Coenzyme A Ligases) RN - EC 6.2.1.3 (ACSL1 protein, human) RN - IY9XDZ35W2 (Glucose) RN - SAA04E81UX (Coenzyme A) SB - IM MH - Animals MH - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*metabolism MH - Coenzyme A/metabolism MH - Coenzyme A Ligases/*genetics MH - Glucose/metabolism/pharmacology MH - Humans MH - *Hyperglycemia/genetics/metabolism MH - Inflammation/genetics/*metabolism MH - Lipopolysaccharides/metabolism/pharmacology MH - Macrophages/metabolism MH - Mice MH - *NF-kappa B/metabolism MH - NF-kappa B p50 Subunit/*metabolism MH - RNA, Messenger/genetics PMC - PMC9439225 COIS- The authors have declared that no competing interests exist. EDAT- 2022/09/03 06:00 MHDA- 2022/09/09 06:00 PMCR- 2022/09/02 CRDT- 2022/09/02 13:43 PHST- 2021/10/22 00:00 [received] PHST- 2022/08/01 00:00 [accepted] PHST- 2022/09/02 13:43 [entrez] PHST- 2022/09/03 06:00 [pubmed] PHST- 2022/09/09 06:00 [medline] PHST- 2022/09/02 00:00 [pmc-release] AID - PONE-D-21-33385 [pii] AID - 10.1371/journal.pone.0272986 [doi] PST - epublish SO - PLoS One. 2022 Sep 2;17(9):e0272986. doi: 10.1371/journal.pone.0272986. eCollection 2022.