Abstract
Intestinal epithelial cell derived alkaline phosphatase (IAP) dephosphorylates/detoxifies bacterial endotoxin lipopolysaccharide (LPS) in the gut lumen. We have earlier demonstrated that consumption of high‐fat high‐cholesterol containing western type‐diet (WD) significantly reduces IAP activity, increases intestinal permeability leading to increased plasma levels of LPS and glucose intolerance. Furthermore, oral supplementation with curcumin that increased IAP activity improved intestinal barrier function as well as glucose tolerance. To directly test the hypothesis that targeted increase in IAP would protect against WD‐induced metabolic consequences, we developed intestine‐specific IAP transgenic mice where expression of human chimeric IAP is under the control of intestine‐specific villin promoter. This chimeric human IAP contains domains from human IAP and human placental alkaline phosphatase, has a higher turnover number, narrower substrate specificity, and selectivity for bacterial LPS. Chimeric IAP was specifically and uniformly overexpressed in these IAP transgenic (IAPTg) mice along the entire length of the intestine. While IAP activity reduced from proximal P1 segment to distal P9 segment in wild‐type (WT) mice, this activity was maintained in the IAPTg mice. Dietary challenge with WD impaired glucose tolerance in WT mice and this intolerance was attenuated in IAPTg mice. Significant decrease in fecal zonulin, a marker for intestinal barrier dysfunction, in WD fed IAPTg mice and a corresponding decrease in translocation of orally administered nonabsorbable 4 kDa FITC dextran to plasma suggests that IAP overexpression improves intestinal barrier function. Thus, targeted increase in IAP activity represents a novel strategy to improve WD‐induced intestinal barrier dysfunction and glucose intolerance.
Highlights
High-fat and high-cholesterol containing western type diet (WD)-induced obesity remains one of the major causes for the development of metabolic syndrome and associated diseases such as type 2 diabetes (T2DM) and coronary artery disease
On the basis of the observed WD-induced reduction in intestinal intestinal alkaline phosphatase (IAP) and subsequent increase in intestinal permeability leading to glucose intolerance, in this study we sought to examine the effects of intestine-specific transgenic overexpression of IAP
We report the successful development of intestine-specific IAP transgenic mice with uniform expression and activity of human chimeric IAP along the intestine
Summary
High-fat and high-cholesterol containing western type diet (WD)-induced obesity remains one of the major causes for the development of metabolic syndrome and associated diseases such as type 2 diabetes (T2DM) and coronary artery disease. Selective decontamination of the gut or oral supplementation with curcumin significantly improved the intestinal barrier function in WD fed LDLR-/- mice resulting in decreased translocation of gutderived LPS into systemic circulation (Ghosh et al 2014). This led to improved glucose tolerance and attenuated atherosclerosis without affecting plasma lipid profiles providing direct evidence that intestine is likely the “first line of defense” against the metabolic consequences of WD and targeted improvement of intestinal barrier function may represent a novel strategy to attenuate WD-induced metabolic diseases
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