Berge R K, Tronstad K J, Berge K, Rost T H, Wergedahl H, Gudbrandsen O A, Skorve J
Institute of Medicine, The Lipid Research Group, Haukeland University Hospital, University of Bergen, 5021 Bergen, Norway.
Biochimie. 2005 Jan;87(1):15-20. doi: 10.1016/j.biochi.2004.11.011.
Much data indicates that lowering of plasma triglyceride levels by hypolipidemic agents is caused by a shift in the liver metabolism towards activation of peroxisome proliferator activated receptor (PPAR)alpha-regulated fatty acid catabolism in mitochondria. Feeding rats with lipid lowering agents leads to hypolipidemia, possibly by increased channeling of fatty acids to mitochondrial fatty acid oxidation at the expense of triglyceride synthesis. Our hypothesis is that increased hepatic fatty acid oxidation and ketogenesis drain fatty acids from blood and extrahepatic tissues and that this contributes significantly to the beneficial effects on fat mass accumulation and improved peripheral insulin sensitivity. To investigate this theory we employ modified fatty acids that change the plasma profile from atherogenic to cardioprotective. One of these novel agents, tetradecylthioacetic acid (TTA), is of particular interest due to its beneficial effects on lipid transport and utilization. These hypolipidemic effects are associated with increased fatty acid oxidation and altered energy state parameters of the liver. Experiments in PPAR alpha-null mice have demonstrated that the effects hypolipidemic of TTA cannot be explained by altered PPAR alpha regulation alone. TTA also activates the other PPARs (e.g., PPAR delta) and this might compensate for deficiency of PPAR alpha. Altogether, TTA-mediated clearance of blood triglycerides may result from a lowered level of apo C-III, with a subsequently induction of hepatic lipoprotein lipase activity and (re)uptake of fatty acids from very low density lipoprotein (VLDL). This is associated with an increased hepatic capacity for fatty acid oxidation, causing drainage of fatty acids from the blood stream. This can ultimately be linked to hypolipidemia, anti-adiposity, and improved insulin sensitivity.
许多数据表明，降血脂药物降低血浆甘油三酯水平是由于肝脏代谢向线粒体中过氧化物酶体增殖物激活受体（PPAR）α调节的脂肪酸分解代谢激活方向转变所致。用降脂药物喂养大鼠会导致血脂过低，可能是通过增加脂肪酸向线粒体脂肪酸氧化的通量，而以甘油三酯合成为代价。我们的假设是，肝脏脂肪酸氧化和生酮作用的增加会使脂肪酸从血液和肝外组织中排出，这对脂肪量积累的有益影响以及改善外周胰岛素敏感性有显著贡献。为了研究这一理论，我们使用了能将血浆谱从致动脉粥样硬化转变为心脏保护型的修饰脂肪酸。其中一种新型药物十四烷基硫代乙酸（TTA）因其对脂质转运和利用的有益作用而特别受关注。这些降血脂作用与脂肪酸氧化增加以及肝脏能量状态参数的改变有关。在PPARα基因敲除小鼠中进行的实验表明，TTA的降血脂作用不能仅用PPARα调节的改变来解释。TTA还能激活其他PPARs（如PPARδ），这可能弥补了PPARα的不足。总之，TTA介导的血液甘油三酯清除可能是由于载脂蛋白C-III水平降低，随后诱导肝脏脂蛋白脂肪酶活性以及从极低密度脂蛋白（VLDL）中（再）摄取脂肪酸所致。这与肝脏脂肪酸氧化能力的增加有关，导致脂肪酸从血流中排出。这最终可能与降血脂、抗肥胖和改善胰岛素敏感性有关。
