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.
References
[1]
Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, et al. (2011) Heart disease and stroke statistics–2011 update: a report from the American Heart Association. Circulation 123: e18–e209.
[2]
Havel RJ, Hamilton RL (2004) Hepatic catabolism of remnant lipoproteins: Where the action is. Arterioscler Thromb Vasc Biol 24: 213–215.
[3]
Higuchi K, Kitagawa K, Kogishi K, Takeda T (1992) Developmental and age-related changes in apolipoprotein B mRNA editing in mice. J Lipid Res 33: 1753–1764.
[4]
Gardner BN, Small DM (1976) Simultaneous measurement of the pancreatic and biliary response to CCK and secretin. Primate biliary physiology. XIII. Gastroenterology 70: 403–407.
[5]
Aho HJ, Sternby B, Kallajoki M, Nevalainen TJ (1989) Carboxyl ester lipase in human tissues and in acute pancreatitis. Int J Pancreatol 5: 123–134.
[6]
Berge KE, Tian H, Graf GA, Yu L, Grishin NV, et al. (2000) Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290: 1771–1775.
[7]
Repa JJ, Mangelsdorf DJ (2000) The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol 16: 459–481.
[8]
Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK (1994) Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest 93: 1885–1893.
[9]
Uchinami H, Seki E, Brenner DA, D'Armiento J (2006) Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis. Hepatology 44: 420–429.
[10]
Wu D, Yang H, Xiang W, Zhou L, Shi M, et al. (2005) Heterozygous mutation of ataxia-telangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice. J Lipid Res 46: 1380–1387.
[11]
Lin X, Yang H, Zhou LC, Guo ZM (2011) Nrf2-Dependent Induction of NQO1 in Mouse Aortic Endothelial Cells Overexpressing Catalase. Free Radic Biol Med 51: 97–106.
[12]
Jazrawi RP, Northfield TC (1986) Effects of a pharmacological dose of cholecystokinin on bile acid kinetics and biliary cholesterol saturation in man. Gut 27: 355–362.
[13]
MacIntosh CG, Morley JE, Wishart J, Morris H, Jansen JB, et al. (2001) Effect of exogenous cholecystokinin (CCK)-8 on food intake and plasma CCK, leptin, and insulin concentrations in older and young adults: evidence for increased CCK activity as a cause of the anorexia of aging. J Clin Endocrinol Metab 86: 5830–5837.
[14]
Iqbal J, Hussain MM (2005) Evidence for multiple complementary pathways for efficient cholesterol absorption in mice. J Lipid Res 46: 1491–1501.
[15]
Tomkin GH, Owens D (2012) The chylomicron: relationship to atherosclerosis. Int J Vasc Med 2012: 784536.
[16]
Ables GP, Yang KJ, Vogel S, Hernandez-Ono A, Yu S, et al. (2012) Intestinal DGAT1 deficiency markedly reduces postprandial triglyceride and retinyl ester excursions by inhibiting chylomicron secretion and delaying gastric emptying. J Lipid Res
[17]
Narisawa S, Huang L, Iwasaki A, Hasegawa H, Alpers DH, et al. (2003) Accelerated fat absorption in intestinal alkaline phosphatase knockout mice. Mol Cell Biol 23: 7525–7530.
[18]
Hussain MM (2000) A proposed model for the assembly of chylomicrons. Atherosclerosis 148: 1–15.
[19]
Berna MJ, Jensen RT (2007) Role of CCK/gastrin receptors in gastrointestinal/metabolic diseases and results of human studies using gastrin/CCK receptor agonists/antagonists in these diseases. Curr Top Med Chem 7: 1211–1231.
[20]
Kaplita PV, Roebuck BD (1984) Proglumide antagonizes the stimulation of rabbit gallbladder by cholecystokinin. Arch Int Pharmacodyn Ther 269: 271–276.
[21]
Calandra S, Tarugi P, Speedy HE, Dean AF, Bertolini S, et al. (2011) Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk. J Lipid Res 52: 1885–1926.
[22]
Wang DQ, Schmitz F, Kopin AS, Carey MC (2004) Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis. J Clin Invest 114: 521–528.
[23]
Miyasaka K, Kanai S, Ohta M, Sekime A, Akimoto S, et al. (2007) Susceptibility to obesity and gallbladder stasis produced by a protein- and fat-enriched diet in male mice compared with female mice. Nutr Metab (Lond) 4: 14.
[24]
Nakajima K, Nakano T, Tokita Y, Nagamine T, Inazu A, et al. (2011) Postprandial lipoprotein metabolism: VLDL vs chylomicrons. Clin Chim Acta 412: 1306–1318.
[25]
Cartwright IJ, Plonne D, Higgins JA (2000) Intracellular events in the assembly of chylomicrons in rabbit enterocytes. J Lipid Res 41: 1728–1739.
[26]
Goldstein JL, Brown MS (2009) The LDL receptor. Arterioscler Thromb Vasc Biol 29: 431–438.
[27]
Blacklow SC (2007) Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers. Curr Opin Struct Biol 17: 419–426.
[28]
Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1: 507–537.
[29]
Mulligan JD, Flowers MT, Tebon A, Bitgood JJ, Wellington C, et al. (2003) ABCA1 is essential for efficient basolateral cholesterol efflux during the absorption of dietary cholesterol in chickens. J Biol Chem 278: 13356–13366.
[30]
Wang DQ (2002) Aging per se is an independent risk factor for cholesterol gallstone formation in gallstone susceptible mice. J Lipid Res 43: 1950–1959.
[31]
Flint A, Bradwejn J, Vaccarino F, Gutkowska J, Palmour R, et al. (2002) Aging and panicogenic response to cholecystokinin tetrapeptide: an examination of the cholecystokinin system. Neuropsychopharmacology 27: 663–671.
