RS5444, a novel PPARγ agonist, regulates aspects of the differentiated phenotype in nontransformed intestinal epithelial cells

Lu Chen, Craig R. Bush, Brian M. Necela, Weidong Su, Masahiro Yanagisawa, Panagiotis Z Anastasiadis, Alan P Fields, E Aubrey Thompson

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Peroxisome proliferator-activated receptor-gamma (PPARγ) is expressed in the intestinal epithelium, yet little is known about the physiological role of PPARγ in the small bowel or the effects of PPARγ on small intestinal epithelial cells. The present studies investigate cellular and genomic effects of PPARγ in nontransformed rat intestinal epithelial cells (RIE). These cells were engineered to express mouse PPARγ1, and thereby to model the molecular phenotype that obtains upon induction of PPARγ at the crypt/villus junction in the small intestine. In these studies, we have used a novel third generation thiazolidinedione derivative, RS5444, which activates PPARγ with an EC50 about 1/50th that of rosiglitazone and has no effect on RIE cells that do not express PPARγ. We used Affymetrix oligonucleotide microarrays to identify potential PPARγ-regulated processes in RIE cells, including lipid metabolism, cell proliferation and differentiation, remodeling of the extracellular matrix, cell morphology, cell-cell adhesion, and motility. The genomic profile reflects cellular events that occur following PPARγ activation: RS5444 inhibited culture growth and caused irreversible G1 arrest, but did not induce apoptosis. In addition, RS5444 caused dramatic changes in cellular morphology which were associated with increased motility and diminished cellular adherence, but no increase in the ability of such cells to digest and invade Matrigel. Inhibition of proliferation, cell cycle arrest, increased motility, and altered adherence are aspects of the differentiated phenotype of villus epithelial cells, which withdraw from the cell cycle at the crypt/villus interface, migrate to the villus tips, and are subsequently shed by loss of contact with the epithelium and the underlying extracellular matrix. Our results are consistent with the hypothesis that PPARγ regulates critical aspects of differentiation in the small intestinal epithelium. Many nuclear receptors regulate differentiation. However, our results point to novel effects of PPARγ on cell-cell and cell-matrix interactions, which are not typical of other nuclear receptors.

Original languageEnglish (US)
Pages (from-to)17-32
Number of pages16
JournalMolecular and Cellular Endocrinology
Volume251
Issue number1-2
DOIs
StatePublished - Jun 7 2006

Fingerprint

PPAR gamma
Epithelial Cells
Phenotype
Rats
rosiglitazone
Cell proliferation
Intestinal Mucosa
Cytoplasmic and Nuclear Receptors
Extracellular Matrix
efatutazone
Molecular Models
Cell adhesion
Microarrays
Cell Cycle Checkpoints
Oligonucleotide Array Sequence Analysis
Lipid Metabolism
Cell Adhesion
Oligonucleotides
Cell Communication
Small Intestine

Keywords

  • Differentiation
  • PPAR-gamma
  • Small intestine

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

RS5444, a novel PPARγ agonist, regulates aspects of the differentiated phenotype in nontransformed intestinal epithelial cells. / Chen, Lu; Bush, Craig R.; Necela, Brian M.; Su, Weidong; Yanagisawa, Masahiro; Anastasiadis, Panagiotis Z; Fields, Alan P; Thompson, E Aubrey.

In: Molecular and Cellular Endocrinology, Vol. 251, No. 1-2, 07.06.2006, p. 17-32.

Research output: Contribution to journalArticle

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