Gastroenterology

Gastroenterology

Volume 131, Issue 2, August 2006, Pages 538-553
Gastroenterology

Basic–alimentary tract
PPARβ/δ Regulates Paneth Cell Differentiation Via Controlling the Hedgehog Signaling Pathway

https://doi.org/10.1053/j.gastro.2006.05.004Get rights and content

Background & Aims: All 4 differentiated epithelial cell types found in the intestinal epithelium derive from the intestinal epithelial stem cells present in the crypt unit, in a process whose molecular clues are intensely scrutinized. Peroxisome proliferator–activated receptor β (PPARβ) is a nuclear hormone receptor activated by fatty acids and is highly expressed in the digestive tract. However, its function in intestinal epithelium homeostasis is understood poorly.

Methods: To assess the role of PPARβ in the small intestinal epithelium, we combined various cellular and molecular approaches in wild-type and PPARβ-mutant mice.

Results: We show that the expression of PPARβ is particularly remarkable at the bottom of the crypt of the small intestine where Paneth cells reside. These cells, which have an important role in the innate immunity, are strikingly affected in PPARβ-null mice. We then show that Indian hedgehog (Ihh) is a signal sent by mature Paneth cells to their precursors, negatively regulating their differentiation. Importantly, PPARβ acts on Paneth cell homeostasis by down-regulating the expression of Ihh, an effect that can be mimicked by cyclopamine, a known inhibitor of the hedgehog signaling pathway.

Conclusions: We unraveled the Ihh-dependent regulatory loop that controls mature Paneth cell homeostasis and its modulation by PPARβ. PPARβ currently is being assessed as a drug target for metabolic diseases; these results reveal some important clues with respect to the signals controlling epithelial cell fate in the small intestine.

Section snippets

L-165041

The PPARβ–selective agonist L-165041 (4-[3-[2-propyl-3-hydroxy-4-acetyl] phenoxy] propyloxyphenoxy acetic acid)29 was synthesized in our laboratory but now is available commercially (cat# 422175; Calbiochem; Dormstadt, Germany).

Animals

All animals had free access to a standard laboratory chow diet in a temperature- and light-controlled environment. PPARβ-null mice and their control wild-type were bred on a mixed genetic background (SV129 and C57BL/6) and were killed at 10 weeks of age. After death by CO

Expression Pattern of PPARβ in the Adult Mouse Small Intestine

PPARβ is expressed in all parts of the small intestine in the mouse, with the highest expression in the duodenal mucosa (Figure 1A). It is present mainly in the epithelial cells, with a decreasing gradient of expression from the bottom to the top of the villi (Figure 1B). The highest PPARβ expression is at the bottom of the crypts, with a marked decrease from cell position 9 upward (Figure 1C).

PPARβ-Null Mutation Impairs Paneth Cell Differentiation

In addition to Paneth cells, stem cells (for which the lack of a reliable marker limits determination

Discussion

Our work reveals the importance of the Ihh signaling pathway for Paneth cell maturation and its control by PPARβ. We propose that the intensity of the Ihh signal received by the precursor cells reflects the number of mature Paneth cells in the crypt. High Ihh levels repress maturation of Ptch-1–positive cells, confining them in their precursor state, whereas a weaker hedgehog signal attenuates the positive feedback loop on Ptch-1 expression, driving the terminal differentiation of precursor

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      Numerous trophic factors, including Wnts, fibroblast growth factors (FGFs), serotonin, and Indian hedgehog (Ihh) are known to influence the number of Paneth cells residing at the base of intestinal crypts.15,42,43 In adult small intestine, mature Paneth cells may play a role in specification by steering progenitor cells away from the Paneth cell lineage through Ihh signaling, thereby controlling Paneth cell number.44 Conversely, conditional knockout of Ihh in mouse small intestine results in an increased number of Paneth cells.45,46

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    Present addresses: Department of Cardiology, Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland (P.G.); Department of Cell Physiology and Metabolism, Geneva Medical School, CH-1211 Genève 04, Switzerland (N.B.).

    Supported by the Etat de Vaud, Nestlé Research Center, and grants from the Swiss National Science Foundation (B.D. and W.W.).

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