Phytol/Phytanic Acid and Insulin Resistance: Potential Role of Phytanic Acid Proven by Docking Simulation and Modulation of Biochemical Alterations

Abstract

Since activation of PPARγ is the main target for the antidiabetic effect of TZDs, especially when it heterodimerizes with RXR, we aimed to test the potential antidiabetic effect of phytol (250 mg/kg), the natural precursor of phytanic acid, a RXR ligand and/or pioglitazone (5 mg/kg) to diabetic insulin-resistant rats. Regarding the molecular docking simulation on PPARγ, phytanic acid, rather than phytol, showed a binding mode that mimics the crystal orientation of rosiglitazone and pioglitazone, forming H bonds with the same amino acids (S289, H 323, H 449 and Y 473), and the least energy level, which emphasizes their importance for PPARγ molecular recognition, activation, hence 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). These results were further supported biochemically, where oral phytol and/or pioglitazone (5 mg/kg) improved significantly glucose homeostasis, lipid panel, raised serum adiponectin level and lowered TNF-α, reaching in most cases the effect of the 10 mg/kg pioglitazone. The study concluded that the insulin sensitizing/anti-diabetic effect of phytol is mediated by partly from activation of nuclear receptors and heterodimerization of RXR with PPARγ by phytanic acid.

Warfarin-chlorophyll herb-drug interactions

“…Phytol/phytanic acid, a derivative of chlorophyll, has a potential role in the management of insulin resistance and metabolic disorders that accompany diabetes and/or obesity, through activating the retinoid X receptor. It has been suggested that phytol can be administered with lower doses of thiazolidinediones, the insulin sensitizers, to maintain the full therapeutic action, but with lesser side effects 36 . According to historical use, chlorophyll has been suggested to improve body odor in colostomy patients at doses of 100-200 mg/ day 37,38 .…”

Phytanic acid, a daily consumed chlorophyll-yielded phytol bio-metabolite: A comprehensive review

“…This suggests its potential role in the management of IDDM (Manuel, 2012). It may occur at no or inadequate insulin concentrations (Che et al, 2013); thus there is an indication for insulin resistance pathways by activation of nuclear receptors and heterodimerization of RXR with PPARγ (Elmazar et al, 2013).…”

“…Author ( retinoid X receptor (RXR) and proliferator-activated receptor-gamma (PPARγ), is now considered to have a number of beneficial physiological effects such ascellular growth and differentiation, reproduction, embryonic development (Islam et al, 2015), management of type 2 (insulin dependent) diabetes (Che et al, 2013;Elmazar et al, 2013) and cholesterol lowering (Peter et al, 2014), respectively. In addition, there are also talks for PA mediated anti-teratogenic and mitochondrial membrane permeability (Islam et al, 2015) capabilities.…”

Gc-Ms Study of Two Column Fractions from Methanol Extracts of Loranthus Micranthus and Their In Vivo Antidiabetic Activity on Alloxan Induced Diabetic Rats

“…inhibitors [17][18][19]. Fraction 20 yielded 11 different compunds in which three compunds (ar-tumerone, 3,7,11,15-tetramethyl-2-hexadecenl-ol, trans-13-octadeceboic acid) have already exhibited antidiabetic, α-glucosidase inhibitors [20,21].…”