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We have previously demonstrated that adult pig islets of Langerhans are not destroyed in vitro by primate sera. Whether these islets can function when placed into the liver of non-human primates is not known. We now report on the outcome of pig islet xenotransplantation into five non diabetic primates (four baboons and one macacus fascicularis) receiving intraportally purified adult pig islets. The average number of islet-equivalent per graft was 110,000 (60-180,000). All animals received associations of ATG, cyclosporine or LF 195 (a deoxyspergualin analog), mycophenolate mofetil and corticosteroids. A specific porcine C-peptide (C-pep) RIA test was used to monitor insulin secretion. Two hours after grafting, porcine C-peptide was positive (from 0.37 to 4.25 ng/ml) in all monkeys except one. Primate C-pep was normal in all cases. Only two monkeys had detectable levels of porcine C-pep on day 1 or 2 with undetectable levels thereafter, even after glucagon challenge between days 6 and 10. Several normal islets with moderate inflammatory infiltration were observed in one animal liver on day 2 (the time of necropsy) as well as islets with IgM and complement deposition. Among animals sacrificed on days 14, 16 and 38, some residual islet cells could be identified only in livers collected on day 14. Partial glycaemic control was achieved in some rats receiving islets from the same preparations. In conclusion, adult pig islets are not able to maintain insulin secretion for more than 24 h when injected intraportally into non diabetic immunosuppressed monkeys. suggesting immediate islet xenograft destruction.

Objective-Transintestinal cholesterol excretion (TICE) is an alternate pathway to hepatobiliary secretion. Our study aimed at identifying molecular mechanisms of TICE. Approach and Results-We studied TICE ex vivo in mouse and human intestinal explants, and in vivo after bile diversion and intestinal cannulation in mice. We provide the first evidence that both low-density lipoprotein (LDL) and high-density lipoprotein deliver cholesterol for TICE in human and mouse jejunal explants at the basolateral side. Proprotein convertase subtilisin kexin type 9 (PCSK9) −/− mice and intestinal explants show increased LDL-TICE, and acute injection of PCSK9 decreases TICE in vivo, suggesting that PCSK9 is a repressor of TICE. The acute repression was dependent on the LDL receptor (LDLR). Further, TICE was increased when mice were treated with Lovastatin. These data point to an important role for LDLR in TICE. However, LDLR −/− mice showed increased intestinal LDL uptake, contrary to what is observed in the liver, and tended to have higher TICE. We interpret these data to suggest that there might be at least 2 mechanisms contributing to TICE; 1 involving LDL receptors and other unidentified mechanisms. Acute modulation of LDLR affects TICE, but chronic deficiency is compensated for most likely by the upregulation of the unknown mechanisms. Using mice deficient for apical multidrug active transporter ATP-binding cassette transporter B1 a and b, and its inhibitor, we show that these apical transporters contribute significantly to TICE. Conclusions-TICE is operative in human jejunal explants. It is a metabolically active process that can be acutely regulated, inversely related to cholesterolemia, and pharmacologically activated by statins. Beside the liver, LDLR is expressed in many tissues, including the intestine where it is localized on the basolateral side of enterocytes.13 Experiments in rats infused with LDL showed that intestinal LDLR mediates 60% of the LDL uptake. 14In the liver and in the intestine, the quantity of cell surface LDLR results from a balance between its synthesis and degradation. Cellular cholesterol depletion and cholesterol synthesis inhibitors like statins increase the LDLR transcription via the activation of the sterol response element binding protein 2 pathway.11 Plasma proprotein convertase subtilisin kexin type 9 (PCSK9) induces the LDLR degradation because it binds to the extracellular domain of the LDLR and prevents its recycling to the cell surface.15 Thus, mice deficient in PCSK9 have more LDLR protein in the liver 16 and in the intestine. 17 The functional importance of intestinal LDLR and its circulating regulator PCSK9 in TICE remains to be explored.Efflux of free cholesterol from the apical side of the enterocytes mainly takes place via ATP-binding cassette transporter G5/ATP-binding cassette transporter G8 (ABCG5/G8).18 TICE is reduced by only 40% in ABCG5-deficient mice, 8 suggesting that TICE-derived cholesterol exit enterocytes via other cholesterol transporters. P-Glycoprotein (P-gp; m...