Cholecystokinin Elevates Mouse Plasma Lipids

Abstract

Cholecystokinin (CCK) is a peptide hormone that induces bile release into the intestinal lumen which in turn aids in fat digestion and absorption in the intestine. While excretion of bile acids and cholesterol into the feces eliminates cholesterol from the body, this report examined the effect of CCK on increasing plasma cholesterol and triglycerides in mice. Our data demonstrated that intravenous injection of [Thr28, Nle31]-CCK at a dose of 50 ng/kg significantly increased plasma triglyceride and cholesterol levels by 22 and 31%, respectively, in fasting low-density lipoprotein receptor knockout (LDLR−/−) mice. The same dose of [Thr28, Nle31]-CCK induced 6 and 13% increases in plasma triglyceride and cholesterol, respectively, in wild-type mice. However, these particular before and after CCK treatment values did not achieve statistical significance. Oral feeding of olive oil further elevated plasma triglycerides, but did not alter plasma cholesterol levels in CCK-treated mice. The increased plasma cholesterol in CCK-treated mice was distributed in very-low, low and high density lipoproteins (VLDL, LDL and HDL) with less of an increase in HDL. Correspondingly, the plasma apolipoprotein (apo) B48, B100, apoE and apoAI levels were significantly higher in the CCK-treated mice than in untreated control mice. Ligation of the bile duct, blocking CCK receptors with proglumide or inhibition of Niemann-Pick C1 Like 1 transporter with ezetimibe reduced the hypercholesterolemic effect of [Thr28, Nle31]-CCK in LDLR−/− mice. These findings suggest that CCK-increased plasma cholesterol and triglycerides as a result of the reabsorption of biliary lipids from the intestine.

Up-regulation of Cholesterol Absorption Is a Mechanism for Cholecystokinin-induced Hypercholesterolemia

“…The CCK concentrations in these mice were elevated ϳ30% at 30 min after injection of 50 ng/kg [Thr 28 ,Nle 31 ]CCK and returned to the basal level 2 h after injection (7). We also observed that the plasma cholesterol levels in CCK-treated wild-type and LDLR Ϫ/Ϫ mice were ϳ13 and 31% higher, respectively, than their vehicle-treated controls (7). Similarly, data from this report show that the plasma cholesterol level was elevated by ϳ21 and 37% in wild-type and LDLR Ϫ/Ϫ mice, respectively, after an intravenous injection of 50 ng/kg [Thr 28 ,Nle 31 ]CCK (Fig.…”

“…The plasma cholesterol in wild-type mice is distributed mostly in HDL, whereas knockout of LDLR mainly elevates LDL and VLDL cholesterol (7,23). The data in Fig.…”

“…At ϳ4 months of age, mice were starved overnight and placed into one of two different but related studies. In the first study, wild-type and LDLR Ϫ/Ϫ mice were injected with either 50 ng/kg [Thr 28 ,Nle 31 ]CCK or 50 l of phosphate-buffered saline (PBS) via the tail vein under ketamine anesthesia as described previously (7). About 20 l of blood was collected by retro-orbital bleeding before and 2 h after the injection of CCK.…”

“…The radioactivity in the liver, plasma, and FPLC fractions was determined by liquid scintillation counting (9). The radioactivity in various lipoproteins was calculated using the FPLC fractions, as we described previously (7,9).…”

“…A recent report from our laboratory showed that intravenous injection of [Thr 28 ,Nle 31 ]cholecystokinin (CCK) significantly elevated the plasma cholesterol level in fasting low density lipoprotein receptor knock-out (LDLR Ϫ/Ϫ ) mice (7). Ligation of the bile duct, blocking CCK receptors with proglumide, or inhibition of the Niemann-Pick C1-like 1 transporter with ezetimibe reduced the hypercholesterolemic effect of CCK on LDLR Ϫ/Ϫ mice (7).…”