Biological Evaluation of Natural and Synthesized Homovanillic Acid Esters as Inhibitors of Intestinal Fatty Acid Uptake in Differentiated Caco-2 Cells

Abstract

With raising prevalence of obesity, the regulation of human body fat is increasingly relevant. The modulation of fatty acid uptake by enterocytes represents a promising target for body weight maintenance. Recent results demonstrated that the trigeminal active compounds capsaicin, nonivamide, and trans-pellitorine dose-dependently reduce fatty acid uptake in differentiated Caco-2 cells as a model for the intestinal barrier. However, non-pungent alternatives have not been investigated and structural determinants for the modulation of intestinal fatty acid uptake have not been identified so far. Thus, based on the previous results, we synthesized 23 homovanillic acid esters in addition to the naturally occurring capsiate and screened them for their potential to reduce intestinal fatty acid uptake using the fluorescent fatty acid analog Bodipy-C12 in differentiated Caco‑2 cells as an enterocyte model. Whereas pre-incubation with 100 µM capsiate did not change fatty acid uptake by Caco-2 enterocytes, a maximum inhibition of −47% was reached using 100 µM 1‑methylpentyl-2-(4-hydroxy-3-methoxy-phenyl)acetate. Structural analysis of the 24 structural analogues tested in the present study revealed that a branched fatty acid side chain, independent of the chain length, is one of the most important structural motifs associated with inhibition of fatty acid uptake in Caco-2 enterocytes. The results of the present study may serve as an important basis for designing potent dietary inhibitors of fatty acid uptake.

The gut microbiota metabolite capsiate promotes Gpx4 expression by activating TRPV1 to inhibit intestinal ischemia reperfusion-induced ferroptosis

“…A group has uncovered that CAT affects intestinal fatty acid intake. 25 In addition CAT administration was suggested to improve glucose tolerance, prevent obesity and hepatic steatosis, and improve bowel changes caused by a high-fat diet. 26 Zhang et al found that CAT can reduce the blood sugar level of rats with streptozotocin-induced diabetes by increasing rat insulin level and glycogen content, but the effect was weaker than that of capsaicin.…”

Prediction of antifungal activity, cytotoxicity risks and molecular docking against <em>Malassezia furfur</em> of constituents of citronella essential oil (<em>Cymbopogon winterianus</em>)

“…Initially, 15 molecules were designed and optimized in software HyperChem 7.5 TM (RMS 0.1 kcal.Å-1.mol-1 in 800 cycles) [1] using molecular mechanics (MM +) and the semiempirical method (AM1). These molecules were then imported into a biological activity model developed in the free software KNIME Analytics Platform 3.7 [2,3], where RandomForest was used as a classifier and Weka 3.7 as a predictor. Consequently, the molecules were classified as active and inactive.…”

One-Pot Efficient Biosynthesis of 4-Hydroxyphenylacetic Acid and Its Analogues from Lignin-Related p-Coumaric and Ferulic Acids

“…Homovanillic acid has long been used as an indicator to facilitate the detection and diagnosis of many diseases, including Parkinson’s disease and catecholamine-secreting tumors . Moreover, its esters are potentially inhibitors of fatty acid uptake to promote the body weight maintenance . These beneficial properties could increase the demand for the synthesis of these phenolic acids.…”

“…Phenol and hydroxymandelic acid can also be used to synthesize 4-hydroxyphenylacetic acid, but these methods suffer from low yield and the requirement of expensive solvents, respectively. , 3,4-Dihydroxyphenylacetic acid can be produced by the electrochemical conversion of phenylacetic acid, which results in difficult separation and purification owing to the formation of a mixture . Homovanillic acid is generally synthesized starting from guaiacol and glyoxylic acid, but this affords low yield and unwanted byproduct . Fortunately, developments in biocatalysis have addressed the abovementioned issues.…”

“…11 Moreover, its esters are potentially inhibitors of fatty acid uptake to promote the body weight maintenance. 12 These beneficial properties could increase the demand for the synthesis of these phenolic acids. 4-Hydroxyphenylacetic acid and its analogues can be extracted directly from natural sources, but this method has its limitations including low abundance and environmental concerns.…”