Effect of Synthetic Truncated Apolipoprotein C-I Peptide on Plasma Lipoprotein Cholesterol in Nonhuman Primates

Abstract

The present studies were conducted to determine whether a synthetic truncated apoC-I peptide that inhibits CETP activity in baboons would raise plasma HDL cholesterol levels in nonhuman primates with low HDL levels. We used 2 cynomolgus monkeys and 3 baboons fed a cholesterol- and fat-enriched diet. In cynomolgus monkeys, we injected synthetic truncated apoC-I inhibitor peptide at a dose of 20 mg/kg and, in baboons, at doses of 10, 15, and 20 mg/kg at weekly intervals. Blood samples were collected 3 times a week and VLDL $+$ LDL and HDL cholesterol concentrations were measured. In cynomolgus monkeys, administration of the inhibitor peptide caused a rapid decrease in VLDL $+$ LDL cholesterol concentrations (30%-60%) and an increase in HDL cholesterol concentrations (10%-20%). VLDL $+$ LDL cholesterol concentrations returned to baseline levels in approximately 15 days. In baboons, administration of the synthetic inhibitor peptide caused a decrease in VLDL $+$ LDL cholesterol (20%-60%) and an increase in HDL cholesterol (10%-20%). VLDL $+$ LDL cholesterol returned to baseline levels by day 21, whereas HDL cholesterol concentrations remained elevated for up to 26 days. ApoA-I concentrations increased, whereas apoE and triglyceride concentrations decreased. Subcutaneous and intravenous administrations of the inhibitor peptide had similar effects on LDL and HDL cholesterol concentrations. There was no change in body weight, food consumption, or plasma IgG levels of any baboon during the study. These studies suggest that the truncated apoC-I peptide can be used to raise HDL in humans.

Figure 1

Effect of truncated apoC-I peptide on the mass transfer of cholesteryl ester from HDL to VLDL + LDL in reconstitute assays ($n=6$). The cholesteryl ester transfer in the plasma was measured by adding the truncated apoC-I peptide at a concentration of 25 μM, as described in “methods.” The decrease in cholesteryl ester transfer in plasma added with the truncated peptide (peptide) has been expressed as the percent of transfer in the plasma without the truncated peptide (control).

Figure 2

Average percent change in plasma HDL (Δ) and VLDL + LDL (∇) cholesterol concentrations in cynomolgus monkeys after a single injection of the truncated apoC-I peptide at 20 mg/kg on day 0 (arrow). Monkeys were fed the HCHF diet. Values are expressed as mean±SE, $n=2$. Values significantly different from those at day 0 are marked by an asterisk ($P<.05$).

Figure 3

Average percent changes in plasma apoB concentrations in cynomolgus monkeys (∇) after a single injection of the truncated apoC-I peptide at 20 mg/kg on day 0 (arrow). Monkeys were fed the HCHF diet. Values are expressed as mean±SE, $n=2$. Values significantly different from those at day 0 are marked by an asterisk ($P<.05$).

Figure 4

Average percent change in HDL (Δ) and VLDL + LDL (∇) cholesterol concentrations in baboons after subcutaneous injections of the truncated apoC-I peptide at 10, 15, and 20 mg/kg on days 0, 7, and 14, respectively (arrows). The baboons were fed the HCHF diet. Values are expressed as mean±SE, $n=3$. Values significantly different from those at day 0 are marked by an asterisk ($P<.05$).

Figure 5

Average percent change in HDL (Δ) and VLDL + LDL (∇) cholesterol concentrations in baboons after intravenous injections of the truncated apoC-I peptide at 10, 15, and 20 mg/kg on days 0, 7, and 14, respectively (arrows). The baboons were fed the HCHF diet. Values are expressed as mean±SE, $n=3$. Values significantly different from those at day 0 are marked by an asterisk ($P<.05$).

Figure 6

Average percent change in apolipoprotein A-I (∇) and apolipoprotein E (Δ) concentrations in baboons after intravenous injections of the truncated apoC-I peptide at 10, 15, and 20 mg/kg on days 0, 7, and 14, respectively (arrows). The baboons were fed the HCHF diet. Values are expressed as mean±SE, $n=3$. Values significantly different from those at day 0 are marked by an asterisk ($P<.05$).

Figure 7

Average percent change in plasma triglyceride concentrations in baboons after intravenous injections of the truncated apoC-I peptide at 10, 15, and 20 mg/kg at days 0, 7, and 14, respectively (arrows). The baboons were fed the HCHF diet. Values are expressed as mean±SE, $n=3$. Values significantly different from those at day 0 are marked by an asterisk ($P<.05$).