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

Simple Summary Fibrates, such as fenofibrate, are widely used drugs for dyslipidaemia treatment. It is known that they activate peroxisome proliferator-activated receptor alpha (PPAR alpha) which serves as a lipid sensor in the organism. This article addresses how activators and inhibitor of the PPAR alpha could affect differentiation of intestinal cells. Carcinogenesis is a disruption of normal differentiation process and colorectal carcinoma is the third most common cancer in terms of incidence, but the secondp in terms of mortality. One of the important signalling pathways in intestinal cell differentiation as well as carcinogenesis is PI3K/Akt/PTEN. We showed that PPAR alpha activators as well as inhibitor affected the levels of one member of this pathway called phosphatidylinositol-4,5-bisphosphate. This molecule is important for formation of microvilli, the essential structures of fully differentiated intestinal cells. We investigated the effects of PPAR alpha activators fenofibrate and WY-14643 as well as the PPAR alpha inhibitor GW6471 on the PI3K/Akt/PTEN pathway of intestinal cell differentiation. Our previous study showed that all these compounds increased the expression of villin, a specific marker of intestinal cell differentiation in HT-29 and Caco2 cells. Our current results confirmed the central role of lipid messenger phosphatidylinositol-4,5-bisphosphate (PIP2), a known player in brush border formation, in mediating the effects of tested PPAR alpha ligands. Although all tested compounds increased its levels, surprisingly, each of them affected different PIP2-metabolizing enzymes, especially the levels of PIP5K1C and PTEN. Moreover, we found a positive relationship between the expression of PPAR alpha itself and PIP2 as well as PIP5K1C. By contrast, PPAR alpha was negatively correlated with PTEN. However, the expression of antigens of interest was independent of PPAR alpha subcellular localization, suggesting that it is not directly involved in their regulation. In colorectal carcinoma tissues we found a decrease in PTEN expression, which was accompanied by a change in its subcellular localization. This change was also observed for the regulatory subunit of PI3K. Taken together, our data revealed that fenofibrate, WY-14643, and GW6471 affected different members of the PI3K/Akt/PTEN pathway. However, these effects were PPAR alpha-independent.

Automated summary

This study revealed that activators and inhibitors of PPAR alpha affect the PI3K/Akt/PTEN pathway in intestinal cell differentiation, highlighting their impact on brush border formation.