Disruption of the murine intestinal alkaline phosphatase geneAkp3impairs lipid transcytosis and induces visceral fat accumulation and hepatic steatosis

Abstract

Intestinal alkaline phosphatase (IAP) is involved in the process of fat absorption, a conclusion confirmed by an altered lipid transport and a faster body weight gain from 10 to 30 wk in both male and female mice with a homozygous null mutation of the IAP coding gene ( Akp3−/− mice). This study was aimed to delineate morphologically and quantitatively the accelerated lipid absorption in male Akp3−/− mice. Feeding a corn oil bolus produced an earlier peak of triacylglycerol in serum (2 vs. 4 h for Akp3−/− and wild-type mice, respectively) and an approximately twofold increase in serum triacylglycerol concentration in Akp3−/− mice injected with a lipolysis inhibitor, Triton WR-1339. A corn oil load induced the threefold enlargement of the Golgi vacuoles in male wild-type mice but not in Akp3−/− mice, indicating that absorbed lipids rarely reached the Golgi complex and that the transcytosis of lipid droplets does not follow the normal pathway in male Akp3−/− mice. Force feeding an exaggerated fat intake by a 30% fat chow for 10 wk induced obesity in both male Akp3−/− and wild-type mice, and therefore no phenotypic difference was observed between the two. On the other hand, the forced high-fat chow induced an 18% greater body weight gain, hepatic steatosis, and visceral fat accumulation in female Akp3−/− mice but not in female wild-type controls. These results provide further evidence that IAP is involved in the regulation of the lipid absorption process and that its absence leads to progressive metabolic abnormalities in certain fat-forced conditions.

Pdx1inactivation restricted to the intestinal epithelium in mice alters duodenal gene expression in enterocytes and enteroendocrine cells

“…Moreover, fatty meals increase the levels of IAP in serum and lymph (15,35). Mice homozygous for Akp3 null mutation showed faster body weight gain when fed a high-fat diet, as well as an increased lipid clearance, after a single oral administration of corn oil (38,40). Together, these findings indicate that IAP is involved in regulating enterocyte lipid absorption in the intestinal mucosa.…”

“…This suggests that intestine-specific Pdx1 inactivation may have an effect on enterocyte differentiation and that this effect may be more profound in some stem cells/crypts than the others, given that IAP is a common marker of enterocyte differentiation and maturation. Of note, Nakano et al (38) reported that the duodenum of Akp3 Ϫ/Ϫ null mutant mice shows considerable residual alkaline phosphatase activity, and subsequently, Narisawa et al (39) …”

Luminal calcium concentration controls intestinal calcium absorption by modification of intestinal alkaline phosphatase activity

“…Its location suggests an involvement in the uptake of nutrients, but its role has not yet been defined. A relationship with the process of fat absorption (4) and preservation of the normal homeostasis of the gut microbiota has been described previously (5) . IAP expression parallels that of other intestinal proteins involved in Ca absorption under vitamin D stimulation: Ca channel TRPV6, calbindin CD 9k , calcium sodium exchanger NCX 1 and Ca pump PMCAb1 (3,6,7) .…”

A dynamic, cytoplasmic triacylglycerol pool in enterocytes revealed by ex vivo and in vivo coherent anti-Stokes Raman scattering imaging

“…In fact, wild-type mice fed a high-fat diet, or challenged with an oil bolus by oral gavage, are commonly reported as having no lipid droplet (LD) accumulation in enterocytes (9)(10)(11). Nevertheless, both indirect and direct evidence exists supporting the presence of a cytoplasmic storage pool in enterocytes.…”