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Cell Metab. 2018 May 1;27(5):1096-1110.e5. doi: 10.1016/j.cmet.2018.03.014. Epub 2018 Apr 19.

Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism.

Author information

1
Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia; Department of Immunology, Monash University, Melbourne, VIC 3004, Australia. Electronic address: graeme.lancaster@baker.edu.au.
2
Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
3
Bioinformatics Institute (A(∗)STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
4
Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
5
Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia.
6
Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; Faculty of Medicine, St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia.
7
Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia; Department of Immunology, Monash University, Melbourne, VIC 3004, Australia.
8
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
9
Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
10
Bioinformatics Institute (A(∗)STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
11
Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia; Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; Faculty of Medicine, St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia. Electronic address: m.febbraio@garvan.org.au.

Abstract

Chronic inflammation is a hallmark of obesity and is linked to the development of numerous diseases. The activation of toll-like receptor 4 (TLR4) by long-chain saturated fatty acids (lcSFAs) is an important process in understanding how obesity initiates inflammation. While experimental evidence supports an important role for TLR4 in obesity-induced inflammation in vivo, via a mechanism thought to involve direct binding to and activation of TLR4 by lcSFAs, several lines of evidence argue against lcSFAs being direct TLR4 agonists. Using multiple orthogonal approaches, we herein provide evidence that while loss-of-function models confirm that TLR4 does, indeed, regulate lcSFA-induced inflammation, TLR4 is not a receptor for lcSFAs. Rather, we show that TLR4-dependent priming alters cellular metabolism, gene expression, lipid metabolic pathways, and membrane lipid composition, changes that are necessary for lcSFA-induced inflammation. These results reconcile previous discordant observations and challenge the prevailing view of TLR4's role in initiating obesity-induced inflammation.

KEYWORDS:

inflammation; innate immunity; metabolism; obesity; toll-like receptors

PMID:
29681442
DOI:
10.1016/j.cmet.2018.03.014

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