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L-Histidine attenuates NEFA-induced inflammatory responses by suppressing Gab2 expression
Mengze Li1, Huiying Wang2, Hanjun Ren1
1State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, PR China.
High non-esterified fatty acids (NEFAs) harm cells, but L-histidine offers protection. This study shows L-histidine counteracts NEFA-induced inflammation by inhibiting Gab2, suggesting therapeutic potential for metabolic issues.
Area of Science:
- Metabolic biochemistry
- Cellular immunology
- Molecular biology
Background:
- Non-esterified fatty acids (NEFAs) are crucial for energy metabolism but can be pathogenic at high levels, potentially triggering immune responses.
- Reduced L-histidine levels in ketotic states, linked to elevated NEFAs, suggest a metabolic interrelation requiring investigation.
Purpose of the Study:
- To investigate the mitigating role of L-histidine against the detrimental effects of NEFAs on Bovine Mammary Epithelial Cells (BMECs).
- To elucidate the molecular mechanisms underlying L-histidine's protective effects, focusing on gene expression and inflammatory pathways.
Main Methods:
- Exposure of BMECs to varying concentrations of NEFAs and L-histidine.
- RNA sequencing to analyze gene expression changes induced by L-histidine.
- EdU incorporation assay to assess cell proliferation.
- Measurement of inflammatory cytokine (IL-6, IL-8) and nitric oxide (NO) levels.
- Investigation of Gab2 (Grb2-associated binder 2) expression and its role in NEFA and L-histidine effects.
Main Results:
- Elevated NEFAs inhibited BMEC proliferation and induced inflammation in a dose-dependent manner.
- L-histidine treatment altered the expression of 2124 genes in BMECs, enriching pathways related to cell cycle and TNF signaling.
- L-histidine increased cell proliferation (EdU-555-positive rate) and suppressed IL-6 and IL-8 levels.
- Concurrent NEFA and L-histidine treatment normalized proliferation and cytokine levels.
- L-histidine reduced NEFA-induced Gab2 expression; Gab2 overexpression increased NO and cytokine production, effects counteracted by L-histidine.
Conclusions:
- L-histidine effectively counteracts NEFA-induced inflammation and proliferation inhibition in BMECs.
- The protective mechanism involves the downregulation of Gab2 expression.
- L-histidine demonstrates therapeutic potential for mitigating NEFA-related metabolic disturbances.
