Saturated Fatty Acids Promote GDF15 Expression in Human Macrophages through the PERK/eIF2/CHOP Signaling Pathway.

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Tytuł:: Saturated Fatty Acids Promote GDF15 Expression in Human Macrophages through the PERK/eIF2/CHOP Signaling Pathway.
Autorzy:: L'homme L; Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, F-59000 Lille, France.; Laboratory of Virology and Immunology, University of Liege, GIGA-Signal Transduction, 4000 Liege, Belgium.
Sermikli BP; Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, F-59000 Lille, France.
Staels B; Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, F-59000 Lille, France.
Piette J; Laboratory of Virology and Immunology, University of Liege, GIGA-Signal Transduction, 4000 Liege, Belgium.
Legrand-Poels S; Laboratory of Virology and Immunology, University of Liege, GIGA-Signal Transduction, 4000 Liege, Belgium.
Dombrowicz D; Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, F-59000 Lille, France.
Źródło:: Nutrients [Nutrients] 2020 Dec 08; Vol. 12 (12). Date of Electronic Publication: 2020 Dec 08.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: Basel, Switzerland : MDPI Publishing
MeSH Terms:: Eukaryotic Initiation Factor-2/*metabolism
Fatty Acids/*pharmacology
Growth Differentiation Factor 15/*metabolism
Macrophages/*metabolism
Signal Transduction/*drug effects
Transcription Factor CHOP/*metabolism
eIF-2 Kinase/*metabolism
Cell Survival/drug effects ; Diet ; Endoplasmic Reticulum Stress/drug effects ; Fatty Acids, Nonesterified ; Fatty Acids, Unsaturated ; Gene Expression Regulation/drug effects ; Growth Differentiation Factor 15/genetics ; Humans ; Lipid Metabolism ; Obesity/metabolism ; RNA, Small Interfering ; THP-1 Cells
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Grant Information:: 694717 International ERC_ European Research Council; ANR-10-LABX-46 Agence Nationale de la Recherche; IAP grant P7/32 Belgian Federal Science Policy Office; FP7-PEOPLE-COFUND-BeIPD FP7 People: Marie-Curie Actions
Contributed Indexing:: Keywords: CHOP; ER stress; GDF15; macrophage; obesity; saturated fatty acids; stearate
Substance Nomenclature:: 0 (DDIT3 protein, human)
0 (Eukaryotic Initiation Factor-2)
0 (Fatty Acids)
0 (Fatty Acids, Nonesterified)
0 (Fatty Acids, Unsaturated)
0 (GDF15 protein, human)
0 (Growth Differentiation Factor 15)
0 (RNA, Small Interfering)
147336-12-7 (Transcription Factor CHOP)
EC 2.7.11.1 (EIF2AK3 protein, human)
EC 2.7.11.1 (eIF-2 Kinase)
Entry Date(s):: Date Created: 20201211 Date Completed: 20210423 Latest Revision: 20220520
Update Code:: 20240104
PubMed Central ID:: PMC7764024
DOI:: 10.3390/nu12123771
PMID:: 33302552
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Growth differentiation factor-15 (GDF-15) and its receptor GFRAL are both involved in the development of obesity and insulin resistance. Plasmatic GDF-15 level increases with obesity and is positively associated with disease progression. Despite macrophages have been recently suggested as a key source of GDF-15 in obesity, little is known about the regulation of GDF-15 in these cells. In the present work, we sought for potential pathophysiological activators of GDF15 expression in human macrophages and identified saturated fatty acids (SFAs) as strong inducers of GDF15 expression and secretion. SFAs increase GDF15 expression through the induction of an ER stress and the activation of the PERK/eIF2/CHOP signaling pathway in both PMA-differentiated THP-1 cells and in primary monocyte-derived macrophages. The transcription factor CHOP directly binds to the GDF15 promoter region and regulates GDF15 expression. Unlike SFAs, unsaturated fatty acids do not promote GDF15 expression and rather inhibit both SFA-induced GDF15 expression and ER stress. These results suggest that free fatty acids may be involved in the control of GDF-15 and provide new molecular insights about how diet and lipid metabolism may regulate the development of obesity and T2D.

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