Saturated fatty acid activates t cell inflammation through a nicotinamide nucleotide transhydrogenase (Nnt)-dependent mechanism

Grace McCambridge, Madhur Agrawal, Alanna Keady, Philip A. Kern, Hatice Hasturk, Barbara S. Nikolajczyk, Leena P. Bharath

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated bioenergetics play in the inflammatory response of immune cells in obesity is untested. Our objective was to determine how free fatty acids (FFAs) regulate inflammation through impacts on mitochondria and redox homeostasis of peripheral blood mononuclear cells (PBMCs). PBMCs from lean subjects were activated with a T cell-specific stimulus in the presence or absence of generally pro-inflammatory palmitate and/or non-inflammatory oleate. Palmitate decreased immune cell expression of NNT, NADPH, and anti-oxidant glutathione, but increased reactive oxygen and proinflammatory Th17 cytokines. Oleate had no effect on these outcomes. Genetic inhibition of NNT recapitulated the effects of palmitate. PBMCs from obese (BMI >30) compared to lean subjects had lower NNT and glutathione expression, and higher Th17 cytokine expression, none of which were changed by exogenous palmitate. Our data identify NNT as a palmitate-regulated rheostat of redox balance that regulates immune cell function in obesity and suggest that dietary or therapeutic strategies aimed at increasing NNT expression may restore redox balance to ameliorate obesity-associated inflammation.

Original languageEnglish
Article number79
JournalBiomolecules
Volume9
Issue number2
DOIs
StatePublished - Feb 2019

Bibliographical note

Funding Information:
Funding: This work was supported by The College of Health Sciences, Merrimack College (LPB), R01DK108056 (BSN), and UL1TR001998 (PAK).

Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Mitochondria
  • Nicotinamide nucleotide transhydrogenase
  • Oleate
  • Palmitate
  • Peripheral blood mononuclear cells
  • Reactive oxygen species
  • Th17 cytokines

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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