Defining the role of DAG, mitochondrial function, and lipid deposition in palmitate-induced proinflammatory signaling and its counter-modulation by palmitoleate

Macrae, Katherine; Stretton, Clare; Lipina, Christopher; Blachnio-Zabielska, Agnieszka; Baranowski, Marcin; Gorski, Jan; Marley, Anna; Hundal, Harinder S.

doi:10.1194/jlr.m036996

Cited by 46NF-κB Signaling PathwaysProtein Kinase Regulation and GTPase SignalingAdipose Tissue and Metabolism

Defining the role of DAG, mitochondrial function, and lipid deposition in palmitate-induced proinflammatory signaling and its counter-modulation by palmitoleate

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Macrae, Katherine, Stretton, Clare, Lipina, Christopher, Blachnio-Zabielska, Agnieszka, Baranowski, Marcin, Gorski, Jan, Marley, Anna, Hundal, Harinder S.·2013·Journal of Lipid Research

DOI 10.1194/jlr.m036996PMC PMC3735935

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Abstract

Chronic exposure of skeletal muscle to saturated fatty acids, such as palmitate (C16:0), enhances proinflammatory IKK-NFκB signaling by a mechanism involving the MAP kinase (Raf-MEK-ERK) pathway. Raf activation can be induced by its dissociation from the Raf-kinase inhibitor protein (RKIP) by diacylglycerol (DAG)-sensitive protein kinase C (PKC). However, whether these molecules mediate the proinflammatory action of palmitate, an important precursor for DAG synthesis, is currently unknown. Here, involvement of DAG-sensitive PKCs, RKIP, and the structurally related monounsaturated fatty acid palmitoleate (C16:1) on proinflammatory signaling are investigated. Palmitate, but not palmitoleate, induced phosphorylation/activation of the MEK-ERK-IKK axis and proinflammatory cytokine (IL-6, CINC-1) expression. Palmitate increased intramyocellular DAG and invoked PKC-dependent RKIP(Ser153) phosphorylation, resulting in RKIP-Raf1 dissociation and MEK-ERK signaling. These responses were mimicked by PMA, a DAG mimetic and PKC activator. However, while pharmacological inhibition of PKC suppressed PMA-induced activation of MEK-ERK-IKK signaling, activation by palmitate was upheld, suggesting that DAG-sensitive PKC and RKIP were dispensable for palmitate's proinflammatory action. Strikingly, the proinflammatory effect of palmitate was potently repressed by palmitoleate. This repression was not due to reduced palmitate uptake but linked to increased neutral lipid storage and enhanced cellular oxidative capacity brought about by palmitoleate's ability to restrain palmitate-induced mitochondrial dysfunction.

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Cox4.1 cellular abundance declines dramatically when the presence of PA in GLC-containing media is raised above 0.4 mM.
“we have shown previously that its cellular abundance declines dramatically when the presence of PA in GLC-containing media is raised above 0.4 mM [17, 31].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [31]

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Mohan, M. L., Vasudevan, N. T., & Prasad, S. V. N. (2017) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000456 · Cited by 21 · see citing works

Authors: Macrae, K., Stretton, C., Lipina, C., Blachnio-Zabielska, A., Baranowski, M., Gorski, J., Marley, A., & Hundal, H. S.
Affiliations: University of Dundee (GB)
Medical University of Białystok (PL)
AstraZeneca (United Kingdom) (GB)
Corresponding author: Hundal, Harinder S.
ORCID: Lipina, Christopher
Baranowski, Marcin
Hundal, Harinder S.
Venue: Journal of Lipid Research
Publisher: Elsevier BV
Published: 2013-09
Volume: 54
Issue: 9
Pages: 2366-2378
ISSN: 0022-2275 (ISSN-L)
DOI: 10.1194/jlr.m036996
PMC: PMC3735935
OpenAlex: W2134785944
Cited by: 46
References: 63
Citations by year: 2026: 2 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 3 · 2020: 6 · 2019: 3 · 2017: 7 · 2016: 4 · 2015: 9 · 2014: 4
FWCI: 1.99
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 2572 d)
Locations: Journal of Lipid Research (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: AstraZeneca
Diabetes UK (10/0004045)
Directorate for Biological Sciences
Biotechnology and Biological Sciences Research Council
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords: palmitate, palmitoleic acid, diacylglycerol, protein kinase C, RKIP, MAPK/ERK pathway, skeletal muscle inflammation, saturated fatty acids, monounsaturated fatty acids, mitochondrial dysfunction, oxidative capacity, inflammatory cytokines, interleukin-6, CINC-1, PMA, fatty acid uptake
MeSH terms: Animals, Biological Transport, Cell Line, Diglycerides, Fatty Acids, Monounsaturated, Inflammation, Mitochondria, Oxygen, Palmitates, Phosphorylation, Protein Kinase C, Signal Transduction, Proto-Oncogene Proteins c-raf, Extracellular Signal-Regulated MAP Kinases, Phosphatidylethanolamine Binding Protein, Rats, I-kappa B Kinase

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Defining the role of DAG, mitochondrial function, and lipid deposition in palmitate-induced proinflammatory signaling and its counter-modulation by palmitoleate

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