On intestinal alkaline phosphatase and its role in high-fat diet-induced obesity
Brand, A.D. van den
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In this thesis, literature available on the adverse effects of a high fat diet on the integrity of the intestinal border is reviewed. In addition, the role of the enzyme alkaline phosphatase mediating in the process of fat absorption is evaluated. Dietary fat is absorbed via the enterocytes in the proximal part of the small intestine. This process of fat uptake is mediated by an enzyme intestinal alkaline phosphatase (IAP). Next to its regulatory role in fat absorption, IAP has immune-related properties. It is able to dephosphorylate bacterial lipopolysaccharide (LPS), thereby reducing its toxicity. However, after consuming a high fat diet (HFD), the composition of the gut microbiota is altered, favoring the presence of the LPS producing gram negative bacteria. Increased levels of LPS can cause a local inflammation, which can alter the epithelial lining of the gut wall by disturbing, for example, the tight junctions between the enterocytes. The HFD-induced rise in LPS levels, but also increased tension in the enterocytes due to the increased fat absorption can result in an increase in membrane permeability. Subsequently, LPS and pathogens can enter the blood, which may eventually result in endotoxemia. Thus, a HFD can cause a local as well as systemic inflammation, next to just an increased fat uptake. The increased level of fatty acids (FA) itself is also linked to a range of pathologies, as FA can interfere with the insulin signaling cascade. Defects in insulin action may result in insulin resistance, which has also been correlated with type 2 diabetes and liver cirrhosis. As IAP has a regulatory role in both fat uptake and LPS detoxification, it has an interesting therapeutic value. Therapeutic IAP may supplement the depletion of IAP due to an increase in fat absorption and LPS levels, induced by a HFD. This may restore the negative regulation IAP has on fat uptake, and may reduce the inflammatory responses initiated by LPS.