Intestine-specific expression of human chimeric intestinal alkaline phosphatase attenuates Western diet-induced barrier dysfunction and glucose intolerance

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.

TNAP: A New Multitask Enzyme in Energy Metabolism

“…In addition, in experimental liver disease induced by bile duct ligation or CCl 4 exposure, oral IAP administration attenuated the compromised intestinal barrier permeability and liver fibrosis, in association with reduced LPS absorption [ 42 ]. Furthermore, intestine-specific overexpression of a chimeric alkaline phosphatase attenuated the metabolic syndrome induced by a western diet [ 43 ]. A second important function proposed for IAP is dephosphorylation of CD36 and modulation of fatty acid (FA) uptake [ 44 , 45 ].…”

Intestinal Barrier Dysfunction, Bacterial Translocation and Inflammation: Deathly Triad in Sepsis

“…Exogenous IAP administration was suggested to improve the IB function, while oral or enteral administration of IAP ameliorated the disintegrated IB [116,117]. It was recently reported that high fat, Western-type diet-induced IB dysfunction, improved glucose intolerance, and orally administered IAP improved severe ulcerative colitis patients [118]. Since it was reported that anti-TNFα antibodies and inhibition of myosin light chain kinase (MLCK) prevented the impaired barrier function, treatment with these antibodies and inhibitors was suggested to reduce the severity of inflammatory bowel diseases.…”

Curcumin Formulations and Trials: What’s New in Neurological Diseases

“…By far, the most convenient route of administration of medicines is oral, for subsequent enteral absorption. Following oral administration, ingested curcumin passes through the stomach, where practically no absorption takes place [ 7 ], and it is then detected in the intestine [ 8 , 9 ]. However, curcumin is then metabolized extensively during first-pass metabolism [ 10 ], which results in low bioavailability.…”