When Activator and Inhibitor of PPARα Do the Same: Consequence for Differentiation of Human Intestinal Cells

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-dependent transcription factor that plays a role in various processes including differentiation of several cell types. We investigated the role of PPARα in the differentiation of intestinal cells using HT-29 and Caco2 cell lines as a model as well as human normal colon and colorectal carcinoma tissues. We detected a significant increase in PPARα expression in differentiated HT-29 cells as well as in normal surface colon epithelium where differentiated cells are localised. Thus, it seems that PPARα may play a role in differentiation of intestinal cells. Interestingly, we found that both PPARα activators (fenofibrate and WY-14643) as well as its inhibitor (GW6471) regulated proliferation and differentiation of HT-29 cells in vitro in the same way. Both compounds led to a decrease in proliferation accompanied by a significant increase in expression of villin, intestinal alkaline phosphatase (differentiation markers). Moreover, the same trend in villin expression was observed in Caco2 cells. Furthermore, villin expression was independent of subcellular localisation of PPARα. In addition, we found similar levels of PPARα expression in colorectal carcinomas in comparison to adjacent normal epithelium. All these findings support the hypothesis that differentiation of intestinal epithelium is PPARα-independent.

Lipid Messenger Phosphatidylinositol-4,5-Bisphosphate Is Increased by Both PPARα Activators and Inhibitors: Relevance for Intestinal Cell Differentiation

“…(E) Schematic summary of obtained results. Detected increase in PIP2 observed after fenofibrate, WY-14643, and GW6471 treatment could explain our previous results reported increase in villin expression under the same experimental conditions [18]. The effect of PPARα ligands is illustrated by arrows: green-increase in expression, red-decrease in expression, grey dotted-no effect, red dotted-decrease in expression or no effect (the results differ in HT-29 and Caco2 cell lines).…”

“…Although it has been reported that PPARα plays a role in the differentiation of various cells [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ], the differentiation of intestinal cells seems to be PPARα-independent, as shown in our previous study [ 18 ]. In HT-29 and Caco2 cells lines, administration of PPARα activators as well as a PPARα inhibitor increased the expression of villin.…”

“…11 644 807 001). The results for this assay under the same experimental conditions were published in our previous study [ 18 ] and can be found in supplementary material .…”

“…HT-29 and Caco2 cells (human colorectal carcinomas) were cultured and treated under the same conditions and experimental scheme as we described in our previous study [ 18 ]. The cell lines were originally obtained from American Type Culture Collection and authentication before experiment via STR profiles was performed by the Department of Clinical Genetics, Palacky University Olomouc.…”

“…The aim of this study was to investigate whether the effect of two PPARα activators (fenofibrate and WY-14643) as well as a PPARα inhibitor (GW6471) on levels of PIP2-metabolizing enzymes, namely PIP5K1C, PI3K, and PTEN, as well as PIP2 itself, in HT-29 and Caco2 cells could explain the previously detected increase in villin expression [ 18 ]. Moreover, we investigated whether there could be a link between PPARα expression levels and the levels of the currently studied targets after PPARα ligand treatment.…”