Diabetes 2013 July-27

 

Phytol/Phytanic acid and insulin resistance: potential role of phytanic acid proven by docking simulation and modulation of biochemical alterations.

PLoS One. 2013;8(1):e45638.

Mohamed M. Elmazar§, Hanan S. El-Abhar*,#, Mona F. Schaalan$, Nahla A. Farag$$

§British University in Egypt (BUE), Cairo, Egypt; *,#Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt, $Department of Biochemistry, and $$Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Misr  International University (MIU), Cairo, Egypt.

 

Abstract

Background: Since activation of PPARγ is the main target for the antidiabetic effect of TZDs, especially when it heterodimerizes with RXR, therefore the aim of this study was to test the potential antidiabetic effect of phytol, the natural precursor of phytanic acid, a RXR ligand.

Methods: To this extent the molecular docking simulation of phytol and phytanic acid on PPARγ compared to TZD drugs was studied, as well as on PPARγ/RXR heterodimerization. In addition, the possible antidiabetic activity was further investigated biochemically by the oral administration of phytol (250mg/kg) and/or pioglitazone (5mg/kg) to diabetic insulin-resistant rats for two weeks.

Results: Regarding the molecular docking results, phytanic acid, rather than phytol, showed a binding mode that mimic to the crystal orientation of rosiglitazone and pioglitazone, with the least energy level, compared to each of them. All three compounds form hydrogen bonds with the same amino acids (S289, H 323, H 449 and Y 473), which emphasizes their importance as key determinants required for PPARγ molecular recognition and activation and indicates their significance for the antidiabetic activity. In addition, docking on the RXRα/PPARγ heterodimer, revealed that phytanic acid has higher binding affinity and lesser energy score on RXRα, compared to the original ligand, retinoic acid. Phytanic acid binds by 3H bonds and shares retinoic acid in arginine (R 316), indicating its essential role for the dimer activity. These results were further supported biochemically, where both drugs improved significantly glucose homeostasis and lipid panel. They also raised serum adiponectin level and lowered that of ALT, and TNF-α, as well as visceral and epididymal fat weight. The efficacy  of their combination reached in most cases the effect of pioglitazone 10 mg/kg.

Conclusion: The study concluded that the insulin sensitizing/anti-diabetic effect of phytol is mediated by an interplay between modulated glucose panel, corrected lipid profile, increased adiponectin and decreased TNF-α, ALT and visceral/epididymal fat weight. These effects may result partly from activation of nuclear receptors and heterodimerization of RXR with PPARγ by phytanic acid.

Impact: Phytol has a potential role in the management of insulin resistance and metabolic disorders that accompany diabetes and/or obesity, through activating RXR via its metabolite, and modulating other factors that imply in metabolic disorders. Moreover, molecular docking studies of phytanic acid on the two crystal structures of PPARγ binding protein, and RXRα/PPARγ heterodimer showed good alignment with the experimental findings and verified /confirmed the antidiabetic biological activity of phytol and its active metabolite, phytanic acid. Phytol can be administered with lower doses of TZDs to maintain the full therapeutic action, but with lesser side effects. Therefore, addition of nutraceuticals, at meaningful doses, to antidiabetic agents would have substantial efficacy, and presumably could be used as aids to good glucose tolerance and insulin sensitivity.

PMID: 23300941

 

Docking illustrations:

 

Hanan El-Abhar-1

Figure 1.  The binding mode of phytanic acid into the binding site of PPAR-γ shows that phytanic acid exhibits an ICM score of -111.09 and forms 4 hydrogen bonds shown as white dotted lines (Table 1). These encompass one hydrogen bond between O of carbonyl moiety of carboxylic acid with S-289 of distance 2.17 A, another bond with H323 of distance 2.03 and another two H bonds between O of OH with H- 449 of distance 1.89 A and between H of OH with Y 473 of distances 1.22A, (for interpretation of the references to color in the text, the reader is referred to the web version of this article).

 

Hanan El-Abhar-2

Figure 2. The binding mode of phytanic acid docked in RXR α binding site (left), while PPAR γ is bound with its original  ligand rosiglitazone (right).

 

Hanan El-Abhar-3

Figure 3. The binding mode of phytanic acid into the binding site of RXRα, shows that phytanic acid exhibits an ICM score of -114.75 and forms 3 hydrogen bonds shown as white dotted lines (Table 2).  These include two hydrogen bonds between O of 2-oxo of carboxylic acid moiety with R-316 of distance 1.92 A and 2.15 A, and another bond between O of  2-oxo of carboxylic acid with A-327of distance 2.63 A; (for interpretation of the references to color in the text, the reader is referred to the web version of this article).

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