Memon R A, Shechter I, Moser A H, Shigenaga J K, Grunfeld C, Feingold K R
Department of Medicine, University of California San Francisco, and Department of Veterans Affairs Medical Center, 94121, USA.
J Lipid Res. 1997 Aug;38(8):1620-9.
Recent studies have shown that endotoxin (LPS) administration to Syrian hamsters markedly increased hepatic HMG-CoA reductase activity, protein mass, and mRNA levels, but only produced a modest increase in hepatic cholesterol synthesis, suggesting that LPS may also influence other key enzymes involved in the regulation of cholesterol metabolism. In the present study, we have examined the effect of LPS and cytokines on the activity, protein mass, and mRNA level of squalene synthase, which is the first committed enzyme in cholesterol biosynthesis and is located at a branch point in the mevalonate pathway. Our results demonstrate that LPS administration produces a marked decrease in the mRNA levels of squalene synthase. This decrease in squalene synthase mRNA occurred very rapidly (90 min after LPS) and required relatively small doses of LPS (1 microg/100 gm body weight). LPS also significantly decreased squalene synthase activity and protein mass. Finally, LPS produced a marked decrease in squalene synthase mRNA, activity, and protein levels when the basal levels of squalene synthase expression were increased 4-fold by prior treatment with bile acid binding resin, colestipol. Tumor necrosis factor and interleukin-1, which mediate many of the metabolic effects of LPS, also decreased hepatic squalene synthase activity and mRNA levels. Taken together, our results suggest that the discordant regulation of HMG-CoA reductase and squalene synthase during the host response to infection and inflammation may have substantial effects on the regulation of substrate flux into the non-sterol pathways of mevalonate metabolism.
最近的研究表明，给叙利亚仓鼠注射内毒素（LPS）可显著提高肝脏中HMG-CoA还原酶的活性、蛋白量和mRNA水平，但仅使肝脏胆固醇合成有适度增加，这表明LPS可能还会影响参与胆固醇代谢调节的其他关键酶。在本研究中，我们检测了LPS和细胞因子对鲨烯合酶活性、蛋白量和mRNA水平的影响，鲨烯合酶是胆固醇生物合成中的首个关键酶，位于甲羟戊酸途径的一个分支点。我们的结果表明，注射LPS会使鲨烯合酶的mRNA水平显著降低。鲨烯合酶mRNA的这种降低出现得非常迅速（LPS注射后90分钟），且所需的LPS剂量相对较小（1微克/100克体重）。LPS还显著降低了鲨烯合酶的活性和蛋白量。最后，当通过预先用胆汁酸结合树脂考来替泊处理使鲨烯合酶表达的基础水平增加4倍时，LPS仍使鲨烯合酶的mRNA、活性和蛋白水平显著降低。介导LPS许多代谢作用的肿瘤坏死因子和白细胞介素-1也降低了肝脏鲨烯合酶的活性和mRNA水平。综上所述，我们的结果表明，在宿主对感染和炎症的反应过程中，HMG-CoA还原酶和鲨烯合酶的不协调调节可能对甲羟戊酸代谢非甾醇途径中底物通量的调节产生重大影响。
