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. 2024 Jan 3:102:skae248.
doi: 10.1093/jas/skae248.

In silico analysis of polyphenols modulate bovine PPARγ to increase milk fat synthesis in dairy cattle via the MAPK signaling pathways

Muhammad Safdar  1 , Faizul Hassan  1 , Muhammad Sajjad Khan  1 , Aneeb Hassan Khan  1 , Yasmeen Junejo  1 , Mehmet Ozaslan  2 , Muhammad Asif Arain  3 , Atique Ahmed Behan  4
Affiliations

In silico analysis of polyphenols modulate bovine PPARγ to increase milk fat synthesis in dairy cattle via the MAPK signaling pathways

Muhammad Safdar et al. J Anim Sci. .

Abstract

This study investigates the potential phytochemicals that modulate bovine peroxisome proliferator-activated receptor gamma (PPARγ) and the mitogen-activated protein kinase (MAPK) pathways to enhance milk fat production in dairy animals. Bovine PPARγ, a key member of the nuclear hormone receptor superfamily, plays a vital role in regulating metabolic, cellular differentiation, apoptosis, and anti-inflammatory responses in livestock, while the MAPK pathway is contributory in cellular processes that impact milk fat synthesis. This approach involved an all-inclusive molecular docking analysis of 10,000 polyphenols to identify potential PPARγ ligands. From this extensive screening, top 10 compounds were selected that exhibited the highest binding affinities to bovine PPARγ. Particularly, curcumin sulfate, isoflavone, and quercetin emerged as the most promising candidates. These compounds demonstrated superior docking scores (-9.28 kcal/mol, -9.27 kcal/mol, and -7.31 kcal/mol, respectively) and lower RMSD values compared to the synthetic bovine PPARγ agonist, 2,4-thiazolidinedione (-4.12 kcal/mol), indicating a strong potential for modulating the receptor. Molecular dynamics simulations (MDS) further affirmed the stability of these polyphenols-bovine PPARγ complexes, suggesting their effective and sustained interactions. These polyphenols, known as fatty acid synthase inhibitors, are suggested to influence lipid metabolism pathways crucial to milk fat production, possibly through the downregulation of the MAPK pathway. The screened compounds showed favorable pharmacokinetic profiles, including nontoxicity, carcinogenicity, and high gastrointestinal absorption, positioning them as viable candidates for enhancing dairy cattle health and milk production. These findings may open new possibilities for the use of phytochemicals as feed additives in dairy animals, suggesting a novel approach to improve milk fat synthesis through the dual modulation of bovine PPARγ and MAPK pathways.

Keywords: MAPK signaling pathways; bovine PPARγ; dairy cattle; milk fat synthesis; molecular docking analysis; polyphenols.

Plain language summary

This study explores how certain plant-derived phytochemicals may enhance milk fat production in dairy cattle by modulating the bovine peroxisome proliferator-activated receptor gamma (PPARγ) and Mitogen-Activated Protein Kinase (MAPK) pathways. PPARγ is crucial for metabolic regulation and anti-inflammatory responses, while the MAPK pathway impacts milk fat synthesis. Through the molecular docking analysis, we found 10 compounds out of 10,000 polyphenols with the highest binding affinity with PPARγ ligands. Curcumin sulfate, isoflavone, and quercetin emerged as the most promising, with superior docking scores and stability in molecular dynamics simulations compared to a synthetic PPARγ agonist. These polyphenols, known as fatty acid synthase inhibitors, may influence lipid metabolism pathways crucial to milk fat production by downregulating the MAPK pathway. Additionally, these compounds demonstrated favorable pharmacokinetic profiles, including nontoxicity and high gastrointestinal absorption, making them viable candidates for enhancing dairy cattle health and milk production. This study suggests that phytochemicals could be used as feed additives to improve milk fat synthesis through dual modulation of PPARγ and MAPK pathways.

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Conflict of interest statement

The authors declare no real or perceived conflicts of interest.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Three-dimensional (3D) structure of the Bovine PPARγ receptor, that can be visualized with color coding based on the qualitative model energy analysis (QMEAN) score, which provides insights into the quality of the protein model.
Figure 2.
Figure 2.
Three-dimensional structure for bovine PPARγ protein. Ramchandran plot (a, b) and SWISS-model (c) generated using UCLA-DOE LAB-SAVES V6.0.
Figure 3.
Figure 3.
Docking results of various polyphenols with PPARγ. (A) Docking between curcumin sulphate and bovine PPARγ, (B) docking between isoflavone base + 2O and bovine PPARγ, (C) docking between isomucronulatol 7-O-glucoside and bovine PPARγ, and (D) docking between 3,8,10-trihydroxy-9-(3-methylbut-1-enyl)-6-(2-methylprop-1-enyl)-6H-chromeno[4,3-b] chromen-7-one and bovine PPARγ. (a) 2D interactions, (b) surface view of 3D binding pattern.
Figure 4.
Figure 4.
Docking results of various polyphenols with PPARγ. (A) Docking between oxyfadichalcone A and bovine PPARγ, (B) docking between 1-[2,4-dihydroxy-3-(7-hydroxy-3,7-dimethylocta-2,5-dienyl) phenyl]-3-(4-hydroxyphenyl) prop-2-en-1-one and bovine PPARγ, (C) docking between fleminchalcone A and bovine PPARγ, and (D) docking between lignans and bovine PPARγ. (a) 2D interactions, (b) surface view of 3D binding pattern.
Figure 5.
Figure 5.
Docking results of various polyphenols with PPARγ. (A) Docking between 6-(1-hydroxy-3-phenylprop-2-enylidene)-5-methoxy-2,2-bis(3-methylbut-2-enyl) cyclohex-4-ene-1,3-dione and bovine PPARγ, (B) docking between quercetin 3ʹ-O-sulfate and bovine PPARγ, (C) docking between 2,4-thiazolidinedione (synthetic agonist) and bovine PPARγ. (a) 2D interactions, (b) surface view of 3D binding pattern.
Figure 6.
Figure 6.
RMSD values of the alpha carbon atoms of both the ligands and proteins recorded after regular intervals (ns).
Figure 7.
Figure 7.
Root mean square fluctuation (RMSF) of complexes in angstroms for residue indexes.
Figure 8.
Figure 8.
Radius of gyration of complexes for residue indexes. (a) Interaction of PPAR-γ with curcumin sulfate and (b) interaction with isoflavone.
Figure 9.
Figure 9.
Solvent accessible surface of docked complexes. (a) Interaction of PPARγ with curcumin sulfate and (b) interaction with isoflavone.
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