PPARβ/δ regulates Paneth cell differentiation via controlling the hedgehog signaling pathway
PPARβ/δ regulates Paneth cell differentiation via controlling the hedgehog signaling pathway
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DOI：
10.1053/j.gastro.2006.05.004
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发表时间：
2006-08-01
期刊：
影响因子：
29.4
通讯作者：
Desvergne, Beatrice
中科院分区：
文献类型：
--
作者：
Varnat, Frederic;Bordier-Ten Heggeler, Beatrice;Desvergne, Beatrice
背景和目标：在肠上皮中发现的所有4种分化的上皮细胞类型都来源于存在于隐窝单位中的肠上皮干细胞，其分子线索在一个过程中被严格审查。过氧化物酶体增殖物激活受体0（PPAR β）是一种由脂肪酸激活的核激素受体，在消化道中高度表达。然而，其在肠上皮内稳态中的功能知之甚少。研究方法：为了评估PPARbeta在小肠上皮中的作用，我们在野生型和PPARbeta突变小鼠中结合了各种细胞和分子方法。结果如下：我们发现，在潘氏细胞所在的小肠隐窝底部，过氧化物酶体增殖物激活受体β的表达特别显著。这些在先天免疫中具有重要作用的细胞在PPAR β缺失小鼠中受到显著影响。然后，我们表明，印度刺猬（Ihh）是成熟的潘氏细胞发送到他们的前体，负调控他们的分化的信号。重要的是，PPAR β通过下调Ihh的表达来作用于潘氏细胞的稳态，这种作用可以被已知的刺猬信号通路抑制剂环巴胺模拟。结论：我们解开了IHH依赖的调节环，控制成熟的潘氏细胞的稳态和其调制的过氧化物酶体增殖物激活受体β。目前，PPAR β正被评估为代谢性疾病的药物靶点;这些结果揭示了关于控制小肠上皮细胞命运的信号的一些重要线索。
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 0 (PPAR beta) 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 PPAR beta in the small intestinal epithelium, we combined various cellular and molecular approaches in wild-type and PPAR beta-mutant mice. Results: We show that the expression of PPAR beta 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 PPAR beta-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, PPAR beta 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 PPAR beta. PPAR beta 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.