Ileum-Specific Transgenic Expression of Human Chimeric Intestinal Alkaline Phosphatase (IAP) Attenuates Western Diet (WD)–Induced Barrier Dysfunction and Glucose Intolerance

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 151-OR
Author(s):  
HONGLIANG HE ◽  
SIDDHARTHA S. GHOSH ◽  
PAUL J. YANNIE ◽  
JING WANG ◽  
SHOBHA GHOSH
Keyword(s):  
Alkaline Phosphatase ◽  
Glucose Intolerance ◽  
Western Diet ◽  
Barrier Dysfunction ◽  
Intestinal Alkaline Phosphatase ◽  
Transgenic Expression

scholarly journals Over-Expression of Intestinal Alkaline Phosphatase Attenuates Atherosclerosis

2021 ◽  
Author(s):  
Siddhartha S Ghosh ◽  
Jing Wang ◽  
Paul J Yannie ◽  
Remy C Cooper ◽  
Yashnoor K Sandhu ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Barrier Function ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Lipid Absorption ◽  
Apical Surface ◽  
Barrier Dysfunction ◽  
Intestinal Alkaline Phosphatase ◽  
Over Expression ◽  
Intestinal Barrier Dysfunction

Rationale: Intestinal Alkaline Phosphatase (IAP) is secreted by enterocytes and is present on the apical surface. It not only detoxifies bacterial endotoxin lipopolysaccharide (LPS) in the gut lumen and limits intestinal inflammation but also restricts translocation of LPS into systemic circulation. Diet-induced intestinal barrier dysfunction and subsequent development of metabolic endotoxemia seen in diabetes and heart disease is associated with reduced IAP levels. To examine the direct effects of increased IAP expression on barrier function and development of metabolic diseases, we developed intestine-specific IAP transgenic mice (IAP Tg ) over-expressing human chimeric IAP. Objective: The aim of this study was to evaluate the effects of intestine-specific IAP overexpression on Western-type diet (WD)-induced atherosclerosis in Ldlr -/- mice. Methods and Results: IAPTg mice crossed into Ldlr -/- background (Ldlr-/-IAP Tg ) and Ldlr -/- littermates were fed WD for 16 weeks. Intestinal barrier dysfunction was assessed by monitoring plasma LPS levels and histological examination of colon. Over-expression of IAP attenuated WD-induced disruption of the colonic mucous layer, reducing intestinal barrier dysfunction and plasma LPS levels. Significant reduction in body, liver and adipose tissue weight was also seen in WD-fed Ldlr -/- IAP Tg mice. Plasma and hepatic lipids were also significantly reduced in WD-fed Ldlr -/- IAP Tg mice. Consistently, intestinal lipid absorption was attenuated in Ldlr -/- IAP Tg mice with reduced expression of apical lipid transporters (CD36, FATP4 and NPC1L1) and intracellular lipid transport proteins (FABP1/2, SCP2). Attenuation of WD-induced atherosclerosis in Ldlr -/- IAP Tg mice was demonstrated by significant reduction in arch and total aortic lesions as seen by enface analyses as well as significantly reduced atherosclerotic lesions in the ascending aorta of these mice. Conclusions: IAP overexpression improves intestinal barrier function by maintaining the integrity of the mucin layer in WD fed Ldlr -/- IAPTg mice and attenuates intestinal lipid absorption. Thus, by limiting translocation of gut-derived LPS and/or reducing plasma lipids, over-expression of IAP attenuates development of WD-induced atherosclerosis.

scholarly journals Inhibition of the gut enzyme intestinal alkaline phosphatase may explain how aspartame promotes glucose intolerance and obesity in mice

2017 ◽  
Vol 42 (1) ◽  
pp. 77-83 ◽  
Author(s):  
Sarah S. Gul ◽  
A. Rebecca L. Hamilton ◽  
Alexander R. Munoz ◽  
Tanit Phupitakphol ◽  
Wei Liu ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Weight Loss ◽  
Alkaline Phosphatase ◽  
Glucose Intolerance ◽  
Bowel Loop ◽  
Intestinal Alkaline Phosphatase ◽  
The Metabolic Syndrome ◽  
Significant Difference ◽  
Chronic Model

Diet soda consumption has not been associated with tangible weight loss. Aspartame (ASP) commonly substitutes sugar and one of its breakdown products is phenylalanine (PHE), a known inhibitor of intestinal alkaline phosphatase (IAP), a gut enzyme shown to prevent metabolic syndrome in mice. We hypothesized that ASP consumption might contribute to the development of metabolic syndrome based on PHE’s inhibition of endogenous IAP. The design of the study was such that for the in vitro model, IAP was added to diet and regular soda, and IAP activity was measured. For the acute model, a closed bowel loop was created in mice. ASP or water was instilled into it and IAP activity was measured. For the chronic model, mice were fed chow or high-fat diet (HFD) with/without ASP in the drinking water for 18 weeks. The results were that for the in vitro study, IAP activity was lower (p < 0.05) in solutions containing ASP compared with controls. For the acute model, endogenous IAP activity was reduced by 50% in the ASP group compared with controls (0.2 ± 0.03 vs 0.4 ± 0.24) (p = 0.02). For the chronic model, mice in the HFD + ASP group gained more weight compared with the HFD + water group (48.1 ± 1.6 vs 42.4 ± 3.1, p = 0.0001). Significant difference in glucose intolerance between the HFD ± ASP groups (53 913 ± 4000.58 (mg·min)/dL vs 42 003.75 ± 5331.61 (mg·min)/dL, respectively, p = 0.02). Fasting glucose and serum tumor necrosis factor-alpha levels were significantly higher in the HFD + ASP group (1.23- and 0.87-fold increases, respectively, p = 0.006 and p = 0.01). In conclusion, endogenous IAP’s protective effects in regard to the metabolic syndrome may be inhibited by PHE, a metabolite of ASP, perhaps explaining the lack of expected weight loss and metabolic improvements associated with diet drinks.

scholarly journals The Role of Intestinal Alkaline Phosphatase in Inflammatory Disorders of Gastrointestinal Tract

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Jan Bilski ◽  
Agnieszka Mazur-Bialy ◽  
Dagmara Wojcik ◽  
Janina Zahradnik-Bilska ◽  
Bartosz Brzozowski ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Gastrointestinal Tract ◽  
Intestinal Inflammation ◽  
Stressful Events ◽  
Intestinal Lumen ◽  
Barrier Dysfunction ◽  
Intestinal Alkaline Phosphatase ◽  
Protective Mechanisms ◽  
Brush Border Enzyme

Over the past few years, the role of intestinal alkaline phosphatase (IAP) as a crucial mucosal defence factor essential for maintaining gut homeostasis has been established. IAP is an important apical brush border enzyme expressed throughout the gastrointestinal tract and secreted both into the intestinal lumen and into the bloodstream. IAP exerts its effects through dephosphorylation of proinflammatory molecules including lipopolysaccharide (LPS), flagellin, and adenosine triphosphate (ATP) released from cells during stressful events. Diminished activity of IAP could increase the risk of disease through changes in the microbiome, intestinal inflammation, and intestinal permeability. Exogenous IAP exerts a protective effect against intestinal and systemic inflammation in a variety of diseases and represents a potential therapeutic agent in diseases driven by gut barrier dysfunction such as IBD. The intestinal protective mechanisms are impaired in IBD patients due to lower synthesis and activity of endogenous IAP, but the pathomechanism of this enzyme deficiency remains unclear. IAP has been safely administered to humans and the human recombinant form of IAP has been developed. This review was designed to provide an update in recent research on the involvement of IAP in intestinal inflammatory processes with focus on IBD in experimental animal models and human patients.

scholarly journals Influence of Secretin and Cholecystokinin on Intestinal Alkaline Phosphatase Secretion

1973 ◽  
Vol 64 (4) ◽  
pp. 599-602 ◽  
Author(s):  
Walter P. Dyck ◽  
George A. Martin ◽  
Charles R. Ratliff
Keyword(s):  
Alkaline Phosphatase ◽  
Intestinal Alkaline Phosphatase

scholarly journals Characterization and comparison of soluble and membranous forms of intestinal alkaline phosphatase from the suckling rat.

1981 ◽  
Vol 256 (11) ◽  
pp. 5620-5626
Author(s):  
S.T. Yedlin ◽  
G.P. Young ◽  
B. Seetharam ◽  
S. Seetharam ◽  
D.H. Alpers
Keyword(s):  
Alkaline Phosphatase ◽  
Intestinal Alkaline Phosphatase
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