Laplante Mathieu, Festuccia William T, Soucy Geneviève, Blanchard Pierre-Gilles, Renaud Alexandra, Berger Joel P, Olivecrona Gunilla, Deshaies Yves
Laval Hospital Research Center, Faculty of Medicine, Laval Univ., 2725 Ch Sainte-Foy, Québec, QC, Canada G1V 4G5.
Am J Physiol Regul Integr Comp Physiol. 2009 Jan;296(1):R57-66. doi: 10.1152/ajpregu.90552.2008. Epub 2008 Oct 29.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonism potently reduces circulating triglycerides (TG) in rodents and more modestly so in humans. This study aimed to quantify in vivo the relative contribution of hepatic VLDL-TG secretion and tissue-specific TG clearance to such action. Rats were fed an obesogenic diet, treated with the PPARgamma full agonist COOH (30 mg.kg(-1).day(-1)) for 3 wk, and studied in both the fasted and refed (fat-free) states. Hepatic VLDL-TG secretion rate was not affected by chronic COOH in the fasted state and was only modestly decreased (-30%) in refed rats. In contrast, postprandial VLDL-TG clearance was increased 2.6-fold by COOH, which concomitantly stimulated adipose tissue TG-derived lipid uptake and one of its major determinants, lipoprotein lipase (LPL) activity, in a highly depot-specific manner. TG-derived lipid uptake and LPL were indeed strongly increased in subcutaneous inguinal white adipose tissue and in brown adipose tissue, independently of the nutritional state, whereas of the three visceral fat depots examined (epididymal, retroperitoneal, mesenteric) only the latter responded consistently to COOH. Robust correlations (0.5 < r < 0.9) were observed between TG-derived lipid uptake and LPL in adipose tissues. The agonist did not increase LPL in muscle, and its enhancing action on postprandial muscle lipid uptake appeared to be mediated by post-LPL processes involving increased expression of fatty acid binding/transport proteins (aP2, likely in infiltrated adipocytes, FAT/CD36, and FATP-1). The study establishes in a diet-induced obesity model the major contribution of lipid uptake by specific, metabolically safe adipose depots to the postprandial hypotriglyceridemic action of PPARgamma agonism, and suggests a key role for LPL therein.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂可有效降低啮齿动物的循环甘油三酯（TG）水平，对人类的降低作用则相对较弱。本研究旨在体内量化肝脏极低密度脂蛋白甘油三酯（VLDL-TG）分泌和组织特异性甘油三酯清除对此作用的相对贡献。给大鼠喂食致肥胖饮食，用PPARγ完全激动剂COOH（30 mg·kg⁻¹·天⁻¹）处理3周，并在禁食和再喂食（无脂肪）状态下进行研究。禁食状态下，慢性给予COOH对肝脏VLDL-TG分泌率无影响，再喂食的大鼠中仅适度降低（-30%）。相反，COOH使餐后VLDL-TG清除增加2.6倍，同时以高度储库特异性方式刺激脂肪组织甘油三酯衍生脂质摄取及其主要决定因素之一脂蛋白脂肪酶（LPL）活性。无论营养状态如何，皮下腹股沟白色脂肪组织和棕色脂肪组织中的甘油三酯衍生脂质摄取和LPL确实显著增加，而在所检查的三个内脏脂肪储库（附睾、腹膜后、肠系膜）中，只有后者对COOH有一致反应。在脂肪组织中，甘油三酯衍生脂质摄取与LPL之间观察到强相关性（0.5 < r < 0.9）。激动剂未增加肌肉中的LPL，其对餐后肌肉脂质摄取的增强作用似乎由LPL后过程介导，该过程涉及脂肪酸结合/转运蛋白（aP2，可能在浸润的脂肪细胞中，FAT/CD36和FATP-1）表达增加。该研究在饮食诱导的肥胖模型中确定了特定的、代谢安全的脂肪储库的脂质摄取对PPARγ激动剂餐后降甘油三酯作用的主要贡献，并提示LPL在其中起关键作用。
