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    • Argatroban In the current study we provide

    2023-05-29

    In the current study, we provide evidence that enhanced ATX activity correlates well with increased ATX protein concentration during cholestasis and pregnancy (Fig. 1). Hereby we have ruled out the possibility of ATX enzyme activation in these conditions, e.g. by circulating cholephiles. ATX clearance in mice was, as reported before [19], very rapid but it was unaffected by cholestasis (Fig. 2A). Serum ATX seems to be cleared by endothelial Argatroban (Fig. 2D), but it is likely that the liver is not the only or primary site of clearance, given that serum ATX activity was only slightly lower in vena hepatic compared to vena portae, only in humans reaching an acceptable level of significance (Figs. 2B+C and 3). However, the human samples were obtained during TIPS procedure in cirrhotic patients possibly accompanied by endothelial dysfunction that may underestimate the extent oclearance of ATX by the liver. Similar, yet invasive sampling would have to be collected from cholestatic patients to definitely reject the hypothesis that the increased serum ATX protein level during cholestasis is caused by a decreased clearance in the liver. Organ-specific induction of ATX expression during cholestasis is difficult to investigate in humans. We therefore analyzed organ-specific Atx mRNA expression in mice with experimental cholestasis. We did not observe relevant organ-specific upregulation of Atx mRNA expression in cholestatic compared to control animals (Fig. 4A). However, the increase in serum ATX activity levels in mice was small compared to that in patients (Fig. 7, Fig. 8). A striking difference between mice and men was that Atx mRNA expression was low in small intestine of mice, but impressively high in small intestine of humans (Fig. 4B). Considering the mass of small intestinal tissue relative to total body weight, the small intestine must be regarded as a relevant source of systemic ATX activity in humans. Immunohistochemistry revealed ATX expression in a subset of epithelial cells in the human small intestine (Fig. 5A), showing considerable overlap with chromogranin A (CgA) staining (Fig. 5C). This indicated that intestinal ATX expression is localized in enteroendocrine cells (EECs). EECs have been described as a heterogeneous group of cells with variable and partly overlapping expression patterns for diverse secretory peptides [30], [31]. In our study, most but not all human CgA-positive EECs showed co-staining for ATX (Fig. 5F). Co-staining for a range of endocrine markers (Table 1) did not show sufficient expression overlap to attribute the ATX-positive cells to any of the currently described EEC subpopulations (data not shown). Moreover, no co-expression of ATX with the bile salt receptor TGR5 (Fig. 5D) or the tuft cell marker Dclk1 ([26], data not shown) was found. Thus, ATX expressing cells in the small intestine represent a hitherto unreported subset of EECs (Fig. 5A+C). In small intestine of mice, EECs were present to a similar extent as in humans, as shown by chromogranin A (CgA) expression, but these cells did not show ATX-immunopositivity (Fig. 6A+C). This striking species difference coincides with our observation that in mice serum ATX activity was increased much less during intrahepatic cholestasis (1.9-fold, Fig. 7D) and (cholestatic) pregnancy (2.1-fold, Fig. 8B) than in cholestatic patients (5.5-fold in non-pregnant cholestatic patients with pruritus and 16-fold during ICP [12], [13], as can be derived from Fig. 1. Taken together, we believe small intestinal EECs can be regarded as a major source of serum ATX in humans. The fact that cholestatic mice did show some increase in systemic ATX activity levels suggests that there is an accessory systemic, EEC-independent mechanism of ATX upregulation. The sustained increase in plasma ATX activity levels in our mouse models of intrahepatic (Fig. 7D) but not extrahepatic cholestasis (Fig. 7C), suggests that enterohepatic cycling is crucial here. The observation that pruritus intensity and serum ATX levels rapidly decrease shortly after disruption of the enterohepatic cycle by nasobiliary drainage in patients [12], [13] fits with this hypothesis. Still, therapeutic targeting of small intestinal ATX expression might become a promising anti-pruritic strategy in the future.