Type 2 diabetic patients present high triglyceride and low HDL levels, significant determinants for the risk of atherosclerosis. Transgenic mice overproducing human apolipoprotein (apo)A-II, one of the two major apos of HDLs, display the same lipid disorders. Here, we investigated the possible regulation of apoA-II gene expression by glucose. In primary rat hepatocytes and in HepG2 cells, the transcription of the human apoA-II gene was upregulated by glucose. This response was mediated by a hormone-responsive element within the enhancer of the apoA-II promoter and was dependent on hepatocyte nuclear factor-4␣. Accordingly, in transgenic mice, the human apoA-II gene is stimulated by a high-carbohydrate diet after fasting and at weaning. By contrast, the apoA-II mRNA level is not modified in streptozotocin-induced diabetic rats. In transgenic mice overexpressing the human apoA-II gene, plasma human apoA-II concentration was positively correlated with blood glucose levels. These mice displayed a marked delay in plasma glucose tolerance as compared with control mice. We hypothesize that the following pathogenic pathway might occur in the course of type 2 diabetes: increased apoA-II level causes a rise in plasma triglyceride level and glucose intolerance, resulting in hyperglycemia, which in turn might further increase apoA-II gene transcription. Diabetes 53: [672][673][674][675][676][677][678] 2004

Postprandial hypertriglyceridemia and low plasma HDL levels, which are principal features of the metabolic syndrome, are displayed by transgenic mice expressing human apolipoprotein A-II (hapoA-II). In these mice, hypertriglyceridemia results from the inhibition of lipoprotein lipase and hepatic lipase activities by hapoA-II carried on VLDL. This study aimed to determine whether the association of hapoA-II with triglyceride-rich lipoproteins (TRLs) is sufficient to impair their catabolism. To measure plasma TRL residence time, intestinal TRL production was induced by a radioactive oral lipid bolus. Radioactive and total triglyceride (TG) were rapidly cleared in control mice but accumulated in plasma of transgenic mice, in relation to hapoA-II concentration. Similar plasma TG accumulations were measured in transgenic mice with or without endogenous apoA-II expression. HapoA-II (synthesized in liver) was detected in chylomicrons (produced by intestine). The association of hapoA-II with TRL in plasma was further confirmed by the absence of hapoA-II in chylomicrons and VLDL of transgenic mice injected with Triton WR 1339, which prevents apolipoprotein exchanges. We show that the association of hapoA-II with TRL occurs in the circulation and induces postprandial hypertriglyceridemia. High plasma levels of triglyceride-rich lipoproteins (TRLs) are often associated with low HDL cholesterol concentrations, which are correlated with an increased risk of atherosclerosis (1). More recently, hypertriglyceridemia was also established as an independent risk factor for atherosclerosis, because decreasing plasma triglyceride (TG) without changing HDL and LDL cholesterol levels improved endothelial function (2). On the other hand, hypertriglyceridemia and low plasma HDL levels are features of the metabolic syndrome, a cluster of abnormalities comprising insulin resistance, hypertension, glucose intolerance, abdominal obesity, and the preponderance of small, dense LDLs (3, 4). The metabolic syndrome is diagnosed by the presence of any three of these abnormalities and confers an increased risk of cardiovascular disease.Unexpectedly, we observed that several features of the metabolic syndrome were associated with moderate to high expression of human apolipoprotein A-II (hapoA-II) in transgenic mice generated in our laboratory. The transgenic lines d and l expressing hapoA-II at two and three times the normal concentration, respectively, displayed postprandial hypertriglyceridemia, low plasma HDL and apoA-I levels, and a preponderance of small HDLs rich in hapoA-II (5). The high-expressing l mice also presented mild hypertriglyceridemia after an overnight fast and displayed glucose intolerance (6). Of note, the ratio of hapoA-II to apoA-I in HDL was a key factor regulating the size and number of HDL particles (7). HapoA-II was partly carried by VLDLs in transgenic mice, and apoA-IIcontaining VLDLs were catabolized in vitro by LPL less efficiently than VLDLs from control mice. Moreover, the addition of hapoA-II to posthepar...

We investigated in vivo catabolism of apolipoprotein A-II (apo A-II), a major determinant of plasma HDL levels. Like apoA-I, murine apoA-II (mapoA-II) and human apoA-II (hapoA-II) were reabsorbed in the first segment of kidney proximal tubules of control and hapoA-II-transgenic mice, respectively. ApoA-II colocalized in brush border membranes with cubilin and megalin (the apoA-I receptor and coreceptor, respectively), with mapoA-I in intracellular vesicles of tubular epithelial cells, and was targeted to lysosomes, suggestive of degradation. By use of three transgenic lines with plasma hapoA-II concentrations ranging from normal to three times higher, we established an association between plasma concentration and renal catabolism of hapoA-II. HapoA-II was rapidly internalized in yolk sac epithelial cells expressing high levels of cubilin and megalin, colocalized with cubilin and megalin on the cell surface, and effectively competed with apoA-I for uptake, which was inhibitable by anti-cubilin antibodies. Kidney cortical cells that only express megalin internalized LDL but not apoA-II, apoA-I, or HDL, suggesting that megalin is not an apoA-II receptor. We show that apoA-II is efficiently reabsorbed in kidney proximal tubules in relation to its plasma concentration.-Dugué-Pujol, S