Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism.

Grace Mccambridge,Madhur Agrawal,Barbara Nikolajczyk,Leena Bharath,Alanna Keady,Hatice Hasturk,Philip Kern

doi:10.3390/biom9020079

Grace Mccambridge, Madhur Agrawal + Show 5 more

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https://doi.org/10.3390/biom9020079

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Journal: Biomolecules	Publication Date: Feb 25, 2019
Citations: 20	License type: CC BY 4.0

Affiliation: Merrimack College, University of Kentucky

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.

Highlights

Metabolic diseases like obesity are characterized by mitochondrial dysfunction, redox imbalance, and chronic inflammation
Peripheral blood was obtained from normoglycemic subjects who were lean
Mitochondrial content was similar amongst treatments, as measured by Mitotracker green content was similar amongst treatments, as measured by Mitotracker green fluorescence and expression fluorescence and expression of the inner mitochondrial proteins heat shock protein 60 (Hsp60) and m-aconitase on Western of the inner mitochondrial proteins Hsp60 and m-aconitase on Western blots (Figure 1B–D)

Summary

Introduction

Metabolic diseases like obesity are characterized by mitochondrial dysfunction, redox imbalance, and chronic inflammation. The relationships amongst these physiological changes and how they promote metabolic dysfunction in obesity [1,2] is not well understood. Mitochondria generate cellular reactive oxygen species (ROS) mainly due to respiration-linked electron leakage that generates superoxide anion and other redox changes. These changes are kept in check by anti-oxidants under homeostatic conditions that are required for normal immune function [3]. Such mechanisms may support the unresolved inflammation that associates with obesity complications like type 2 diabetes (T2D) [5]

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