Human apolipoprotein A-II associates with triglyceride-rich lipoproteins in plasma and impairs their catabolism

Abstract

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...

Human Apolipoprotein A-II Determines Plasma Triglycerides by Regulating Lipoprotein Lipase Activity and High-Density Lipoprotein Proteome

“…In a previous report using independently generated hapoA-II-Tg mice, 13 severe postprandial hypertriglyceridemia was associated with a marked increase in plasma hapoA-II concentration in TRL particles, which were found to be poor LPL substrates. 10 In contrast, plasma hapoA-II of our hapoA-II-Tg mice was mainly found associated with HDL during the postprandial state, and we found no nearly complete depletion of the HDL fraction nor a fed-to-fasted switch in hapoA-II concentration. It is possible that the different hapoA-II gene constructions used to generate these 2 hapoA-II-Tg mice 1,13 could explain their differences in hapoA-II plasma concentration regulation in these 2 different transgenic models.…”

“…Evidence favoring a role for apoA-II in TG metabolism stems from experiments in mice [1][2][3][4]10,11 and, also, human studies. 1,[5][6][7][8][9] However, the precise mechanism by which hapoA-II influences TG metabolism remains unclear.…”

“…Mice overexpressing mouse and human apoA-II (hapoA-II) exhibit marked hypertriglyceridemia and increased FFA. 1,10,11 Knocking out of apoA-II in mice decreased plasma TRL concentration and increased remnant catabolism. 12 However, whether apoA-II variability causes increased TRL synthesis, decreases TRL catabolism, or both, remains controversial.…”

“…1 In contrast, an independently generated line of hapoA-II-Tg mice exhibited marked postprandial hypertriglyceridemia, which was associated with an increase in plasma hapoA-II compared to fasted mice, and impaired lipolysis of TRL enriched with hapoA-II. 10,13 To gain more insight into the role of human apoA-II in TG metabolism, we conducted a detailed study of TRL and HDL in our hapoA-II Tg mice and in a group of normolipidemic women. Our data show that accumulation of hapoA-II increases plasma TG through an impaired HDL induction of lipoprotein lipase (LPL) activity that depends, at least in part, on changes induced in the protein composition of discrete HDL subfractions.…”

Impaired anti-inflammatory function of apolipoprotein A-II concentrations predicts metabolic syndrome and diabetes at 4 years follow-up in elderly Turks

“…In apoA-II transgenic mice, human apoA-II is reabsorbed in kidney proximal tubules in relation to its plasma concentration, and then degraded (3). In animals expressing human apoA-II carried by very low-density lipoprotein (LDL), the association of human apoA-II with TRL induces postprandial hypertriglyceridemia due to inhibition of lipoprotein lipase and hepatic lipase activities (4).…”