Falcarindiol Purified From Carrots Leads to Elevated Levels of Lipid Droplets and Upregulation of Peroxisome Proliferator-Activated Receptor-γ Gene Expression in Cellular Models.

Camilla Bertel Andersen,Lars Porskjær Christensen,Morten Østergaard Andersen,Morten Kobaek-Larsen,Richard Cowie,Emma Pipó-Ollé,Martine K Notabi,Martin Aage Barsøe Hedegaard,Adam Leslie Lovatt,Jes Linnet,Sebastian Juul,Anders Runge Walther,Rime El-Houri,Mathias Hessellund Eriksen,Eva Christensen Arnspang

doi:10.3389/fphar.2020.565524

Camilla Bertel Andersen, Lars Porskjær Christensen + Show 13 more

Open Access

https://doi.org/10.3389/fphar.2020.565524

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Abstract

Falcarindiol (FaDOH) is a cytotoxic and anti-inflammatory polyacetylenic oxylipin found in food plants of the carrot family (Apiaceae). FaDOH has been shown to activate PPARγ and to increase the expression of the cholesterol transporter ABCA1 in cells, both of which play an important role in lipid metabolism. Thus, a common mechanism of action of the anticancer and antidiabetic properties of FaDOH may be due to a possible effect on lipid metabolism. In this study, the effect of sub-toxic concentration (5 μM) of FaDOH inside human mesenchymal stem cells (hMSCs) was studied using white light microscopy and Raman imaging. Our results show that FaDOH increases lipid content in the hMSCs cells as well as the number of lipid droplets (LDs) and that this can be explained by increased expression of PPARγ2 as shown in human colon adenocarcinoma cells. Activation of PPARγ can lead to increased expression of ABCA1. We demonstrate that ABCA1 is upregulated in colorectal neoplastic rat tissue, which indicates a possible role of this transporter in the redistribution of lipids and increased formation of LDs in cancer cells that may lead to endoplasmic reticulum stress and cancer cell death.

Highlights

Cancer and diabetes constitute a heavy burden to societies and health care systems globally
We found that treatment with FaDOH leads to increased lipid content and the number of lipid droplet (LD) in the cells, FaDOH treatment increased expression of PPARg2 in HT-29 cells and an increased ATP-binding cassette transporter A1/cholesterol exporter (ABCA1) expression was observed in tumor rat tissue
Close to 100% human mesenchymal stem cells (hMSCs) viability was observed for concentrations between 1 to 20 μM FaDOH and only concentrations above 50 μM exhibited a toxic effect on the cells (Figure 1)

Summary

Introduction

Cancer and diabetes constitute a heavy burden to societies and health care systems globally. We have shown that this antineoplastic effect is most likely due to inhibition of pro-inflammatory markers in the NF-kB signaling pathway such as TNFa, interleukin 6, and cyclooxygenase-2 (Kobaek-Larsen et al, 2019). These polyacetylenes have shown to stimulate basal and insulin-dependent glucose-uptake in cell cultures (El-Houri et al, 2015a). These bioactive secondary metabolites seem to have a preventive effect on the development of both cancer and type 2 diabetes. The question is whether this can be explained by a common mechanism of action and, if so, how this can be utilized to develop dietary supplements and/or drugs to prevent the development of these diseases

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