Feingold K R, Staprans I, Memon R A, Moser A H, Shigenaga J K, Doerrler W, Dinarello C A, Grunfeld C
Department of Medicine, University of California, San Francisco.
J Lipid Res. 1992 Dec;33(12):1765-76.
Hyperlipidemia frequently accompanies infectious diseases and may be due to increases in lipoprotein production or decreases in lipoprotein clearance. The administration of endotoxin (LPS) has been used to mimic infection and prior studies demonstrate that LPS produces hypertriglyceridemia. In the present study in rodents, the dose of LPS necessary to induce hyperlipidemia was orders of magnitude less than that necessary to induce shock and death. As little as 10 ng/100 g body weight induced hypertriglyceridemia and this increase in serum triglyceride levels occurred rapidly (78% increase at 2 h). At high doses of LPS (50 micrograms/100 g body weight), the clearance of triglyceride-rich lipoproteins was decreased. At low doses of LPS (100 ng/100 g body weight), triglyceride clearance was not altered but the hepatic secretion of triglyceride was increased. Low dose LPS stimulated hepatic de novo fatty acid synthesis and lipolysis, both of which provided a source of fatty acids for the increase in hepatic triglyceride production. High dose LPS did not increase hepatic fatty acid synthesis or peripheral lipolysis, and hepatic triglyceride secretion was not stimulated. Thus, low dose LPS produces hypertriglyceridemia by increasing hepatic lipoprotein production, while high dose LPS produces hypertriglyceridemia by decreasing lipoprotein catabolism. Administration of anti-tumor necrosis factor (TNF) antibodies or interleukin 1 (IL-1) receptor antagonist did not prevent the increase in serum triglyceride levels induced by LPS. However, anti-TNF antibodies and interleukin 1 receptor antagonist (IL-1ra) blocked the increase in serum triglycerides induced by TNF or IL-1, respectively. These data suggest that neither of these cytokines is absolutely required for the increase in serum triglycerides induced by LPS, raising the possibility that other cytokines, small molecular mediators, or LPS itself may play a crucial role.
高脂血症常伴随感染性疾病，可能是由于脂蛋白生成增加或脂蛋白清除减少所致。内毒素（LPS）的给药已被用于模拟感染，先前的研究表明LPS会导致高甘油三酯血症。在本项针对啮齿动物的研究中，诱导高脂血症所需的LPS剂量比诱导休克和死亡所需的剂量低几个数量级。低至10 ng/100 g体重即可诱导高甘油三酯血症，血清甘油三酯水平的这种升高迅速发生（2小时时增加78%）。高剂量LPS（50微克/100 g体重）时，富含甘油三酯的脂蛋白清除减少。低剂量LPS（100 ng/100 g体重）时，甘油三酯清除未改变，但肝脏甘油三酯分泌增加。低剂量LPS刺激肝脏从头合成脂肪酸和脂肪分解，这两者都为肝脏甘油三酯生成增加提供了脂肪酸来源。高剂量LPS未增加肝脏脂肪酸合成或外周脂肪分解，也未刺激肝脏甘油三酯分泌。因此，低剂量LPS通过增加肝脏脂蛋白生成导致高甘油三酯血症，而高剂量LPS通过减少脂蛋白分解代谢导致高甘油三酯血症。给予抗肿瘤坏死因子（TNF）抗体或白细胞介素1（IL-1）受体拮抗剂并不能预防LPS诱导的血清甘油三酯水平升高。然而，抗TNF抗体和白细胞介素1受体拮抗剂（IL-1ra）分别阻断了TNF或IL-1诱导的血清甘油三酯升高。这些数据表明，LPS诱导的血清甘油三酯升高并非绝对需要这两种细胞因子，这增加了其他细胞因子、小分子介质或LPS本身可能起关键作用的可能性。
