Kushwaha R S, McGill H C
Department of Physiology and Medicine, Southwest Foundation for Biomedical Research, San Antonio, TX 78245-0549, USA.
Hum Reprod Update. 1998 Jul-Aug;4(4):420-9. doi: 10.1093/humupd/4.4.420.
Diet-induced hyperlipidaemia in baboons is similar to that in humans. As in humans, the ratio between low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol is a major determinant of atherosclerosis. Baboons, like humans and other non-human primates, vary in their lipaemic responses to dietary lipids. By selective breeding based on variability in plasma and lipoprotein cholesterol response to diet, lines of baboons with high and low responses of various lipoproteins have been developed. Genetic analyses suggest that lipoprotein patterns in response to dietary cholesterol and fat are heritable. Metabolic and molecular studies of high and low LDL and HDL cholesterol responses to dietary lipids have suggested that different mechanisms regulate plasma LDL cholesterol on the chow and on the high cholesterol-high fat (HCHF) diet. On the chow diet, plasma LDL cholesterol levels are positively associated with cholesterol absorption and negatively associated with hepatic LDL receptor levels and, thus, cholesterol absorption and LDL receptors seem to regulate plasma LDL cholesterol levels. However, when the animals consume a human-like fat- and cholesterol-enriched diet, plasma LDL cholesterol levels are not associated with either cholesterol absorption or hepatic LDL receptor mRNA levels, but are negatively associated with plasma 27-hydroxycholesterol concentrations, hepatic sterol 27-hydroxylase activity, and mRNA levels. Hepatic sterol 27-hydroxylase activity and mRNA levels are induced by dietary cholesterol and fat in low responding baboons more than in high responding baboons. Thus, the ability to induce sterol 27-hydroxylase determines the LDL cholesterol response in baboons. High HDL response baboons often have high levels of HDL1 in their plasma. Our studies suggest that the N-terminal fragment of apo C-I with 38 amino acids and a molecular weight of approximately 4 kDa acts as a cholesteryl ester transfer inhibitor peptide in high HDL1 baboons. The inhibitor peptide associates with apo A-1 in HDL to produce a modified apo A-1 protein with a molecular weight of approximately 31 kDa. The inhibitor peptide is a gene product and the presence of this peptide produces an antiatherogenic high HDL1 phenotype.
饮食诱导的狒狒高脂血症与人类相似。与人类一样，低密度脂蛋白（LDL）与高密度脂蛋白（HDL）胆固醇的比例是动脉粥样硬化的主要决定因素。狒狒与人类和其他非人类灵长类动物一样，对饮食脂质的血脂反应各不相同。通过基于血浆和脂蛋白胆固醇对饮食反应的变异性进行选择性育种，已培育出各种脂蛋白反应高和低的狒狒品系。遗传分析表明，对饮食胆固醇和脂肪的脂蛋白模式是可遗传的。对高、低LDL和HDL胆固醇对饮食脂质反应的代谢和分子研究表明，不同机制调节普通饮食和高胆固醇高脂肪（HCHF）饮食时的血浆LDL胆固醇。在普通饮食中，血浆LDL胆固醇水平与胆固醇吸收呈正相关，与肝LDL受体水平呈负相关，因此，胆固醇吸收和LDL受体似乎调节血浆LDL胆固醇水平。然而，当动物食用类似人类的富含脂肪和胆固醇的饮食时，血浆LDL胆固醇水平与胆固醇吸收或肝LDL受体mRNA水平均无关联，但与血浆27-羟基胆固醇浓度、肝甾醇27-羟化酶活性和mRNA水平呈负相关。低反应性狒狒的肝甾醇27-羟化酶活性和mRNA水平比高反应性狒狒更易受到饮食胆固醇和脂肪的诱导。因此，诱导甾醇27-羟化酶的能力决定了狒狒的LDL胆固醇反应。高HDL反应性狒狒血浆中通常具有高水平的HDL1。我们的研究表明，具有38个氨基酸且分子量约为4 kDa的载脂蛋白C-I N端片段在高HDL1狒狒中作为胆固醇酯转移抑制肽发挥作用。该抑制肽与HDL中的载脂蛋白A-1结合，产生分子量约为31 kDa的修饰载脂蛋白A-1蛋白。该抑制肽是一种基因产物，该肽的存在产生抗动脉粥样硬化的高HDL1表型。
