Abstract
in the ileal crypts but not EP4 compared to rats fed a regular chow (11.3% kcal/g fat). At the same time, rats on HF demonstrated a strong staining of the unfolded protein response (UPR) transcription factor x-box binding protein-1 (xbp1) (an endoplasmic reticulum stress marker) in the Paneth cells. This was accompanied by a 27% decrease in secretory granules and a significant increase in autophagic vacuoles (1.8 cell vs 0.7 cell in controls; P<0.05) on transmission EM. These changes were associated with fusion of secretory granules, a hallmark of crinophagy and increased staining of microtubule-associated protein 1 light chain 3 (LC3), a marker of autophagosome in the Paneth cells. Quantitative PCR of the ileal crypt showed an increase of autophagy related 16-like 1 (ATG16L1), another hallmark of autophagosome formation. This was accompanied by a 35+4% and 60+9% decrease in alpha-defensin 5 and 6 respectively. To provide direct evidence that PGE2 stimulates the expression of EP2 receptors, we showed that incubation of rat ileum with PGE2 (10 μM) for 6 hrs resulted in a 161% increase in EP2 receptor expression. This was accompanied by a 69% and 57% increase in xbp1, ATG16L1 and a 43% decrease in alpha-defensin 5 (defa 5) expression in the Paneth cells. Our in vivo studies showed that 4 wks oral administration of PF-04418948 (1 mg/kg/day), an EP2 selective antagonist, prevented ER stress and autophagy in the Paneth cell induced by HF. This was evidenced by normalization of xbp1 and ATG16L1 mRNA and defa 5 and 6 expression in the Paneth cells. In conclusion, we showed that HF caused an upregulation of EP2 receptor in the Paneth cells and its activation induced ER stress and autophagy resulting in decreased synthesis in α defensin 5 and 6. Conceivably this may contribute to gut dysbiosis and intestinal inflammation
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