Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism
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...
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| Format: | Article |
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MDPI AG
2019-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/9/2/79 |
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| author | Grace McCambridge Madhur Agrawal Alanna Keady Philip A. Kern Hatice Hasturk Barbara S. Nikolajczyk Leena P. Bharath |
| author_facet | Grace McCambridge Madhur Agrawal Alanna Keady Philip A. Kern Hatice Hasturk Barbara S. Nikolajczyk Leena P. Bharath |
| author_sort | Grace McCambridge |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T19:54:27Z |
| format | Article |
| id | doaj.art-fb911753e26545418386520413d3194a |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-12-20T19:54:27Z |
| publishDate | 2019-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-fb911753e26545418386520413d3194a2022-12-21T19:28:13ZengMDPI AGBiomolecules2218-273X2019-02-01927910.3390/biom9020079biom9020079Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent MechanismGrace McCambridge0Madhur Agrawal1Alanna Keady2Philip A. Kern3Hatice Hasturk4Barbara S. Nikolajczyk5Leena P. Bharath6Department of Nutrition and Public Health, Merrimack College, North Andover, MA 01845, USADepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40506, USADepartment of Nutrition and Public Health, Merrimack College, North Andover, MA 01845, USADepartment of Medicine, University of Kentucky, Lexington, KY 40506, USAForsyth Institute, Cambridge, MA 02142, USADepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40506, USADepartment of Nutrition and Public Health, Merrimack College, North Andover, MA 01845, USACirculating 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.https://www.mdpi.com/2218-273X/9/2/79mitochondrianicotinamide nucleotide transhydrogenaseoleatepalmitateperipheral blood mononuclear cells, reactive oxygen species, Th17 cytokines |
| spellingShingle | Grace McCambridge Madhur Agrawal Alanna Keady Philip A. Kern Hatice Hasturk Barbara S. Nikolajczyk Leena P. Bharath Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism Biomolecules mitochondria nicotinamide nucleotide transhydrogenase oleate palmitate peripheral blood mononuclear cells, reactive oxygen species, Th17 cytokines |
| title | Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism |
| title_full | Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism |
| title_fullStr | Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism |
| title_full_unstemmed | Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism |
| title_short | Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism |
| title_sort | saturated fatty acid activates t cell inflammation through a nicotinamide nucleotide transhydrogenase nnt dependent mechanism |
| topic | mitochondria nicotinamide nucleotide transhydrogenase oleate palmitate peripheral blood mononuclear cells, reactive oxygen species, Th17 cytokines |
| url | https://www.mdpi.com/2218-273X/9/2/79 |
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