Martins I J, Mortimer B C, Redgrave T G
Department of Physiology, University of Western Australia, Nedlands, Perth, Australia.
Arterioscler Thromb Vasc Biol. 1997 Jan;17(1):211-6. doi: 10.1161/01.atv.17.1.211.
Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) activity previously have been found to decrease the absorption of cholesterol and to be effective antiatherosclerotic agents. Effects on chylomicron (CM) transport could contribute to these effects. No previous study has examined the effect of inhibition of ACAT activity on the intestinal lymph output of apolipoprotein (apo) B48 or on the clearance from plasma of lymph CM. In this study, we selected 2,4-difluoro-phenyl-N[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-( hepthyl)urea (CL 277,082) to inhibit intestinal ACAT activity and measured its effects on the output of lipids and apo B48 in intestinal lymph. Compared with control untreated rats, treatment with CL 277,082 decreased the lymph outputs of apo B48 and triglyceride. Associated with the effects on transport, the lymph CM were smaller in diameter in rats treated with CL 277,082. The unesterified cholesterol content of lymph CM was markedly increased and the cholesteryl ester (CE) content was decreased. The contents of triglyceride were decreased and phospholipid was increased. Labeled CM were prepared by feeding donor rats with a test meal containing 3H-cholesterol and 14C-fatty acid. Traced by the CE label in lymph CM in both control rats and rats treated with CL 277,082, the remnants derived after intravenous injection of CM from rats treated with CL 277,082 were cleared significantly more slowly than CM from untreated rats. Moreover, less CE label was recovered in the livers of both groups of rats after injection of CM from rats treated with CL 277,082. Recovery in the spleen was significantly higher in recipient rats injected with CM from rats treated with CL 277,082 when compared with injections of CM obtained from untreated rats. We conclude that the metabolism of CM is affected by treatment with CL 277,082, partly due to the changes in lymph CM composition and partly due to other effects on the recipient rat.
酰基辅酶A：胆固醇酰基转移酶（ACAT）活性抑制剂此前已被发现可降低胆固醇的吸收，并成为有效的抗动脉粥样硬化药物。对乳糜微粒（CM）转运的影响可能有助于产生这些作用。此前尚无研究考察抑制ACAT活性对载脂蛋白（apo）B48肠道淋巴输出或对淋巴CM从血浆中清除的影响。在本研究中，我们选择2,4-二氟苯基-N[[4-(2,2-二甲基丙基)phenyl]甲基]-N-(庚基)脲（CL 277,082）来抑制肠道ACAT活性，并测定其对肠道淋巴中脂质和apo B48输出的影响。与未处理的对照大鼠相比，用CL 277,082处理可降低apo B48和甘油三酯的淋巴输出。与对转运的影响相关，用CL 277,082处理的大鼠中淋巴CM的直径较小。淋巴CM的游离胆固醇含量显著增加，胆固醇酯（CE）含量降低。甘油三酯含量降低，磷脂含量增加。通过给供体大鼠喂食含3H-胆固醇和14C-脂肪酸的试验餐来制备标记的CM。在对照大鼠和用CL 277,082处理的大鼠中，通过淋巴CM中的CE标记追踪发现，静脉注射CL 277,082处理大鼠的CM后产生的残余物清除速度明显慢于未处理大鼠的CM。此外，注射CL 277,082处理大鼠的CM后，两组大鼠肝脏中回收的CE标记较少。与注射未处理大鼠获得的CM相比，注射CL 277,082处理大鼠的CM的受体大鼠脾脏中的回收率显著更高。我们得出结论，CL 277,082处理会影响CM的代谢，部分原因是淋巴CM组成的变化，部分原因是对受体大鼠的其他影响。
