The Danish Diabetes Academy, Aarhus University, Aarhus, Denmark; Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark; and
Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark; and.
Am J Physiol Gastrointest Liver Physiol. 2015 Feb 1;308(3):G198-205. doi: 10.1152/ajpgi.00407.2013. Epub 2014 Dec 4.
The peroxisome proliferator receptor α (PPARα) is a key regulator of the hepatic response to fasting with effects on both lipid and carbohydrate metabolism. A role in hepatic glycerol metabolism has also been found; however, the results are somewhat contradictive. Aquaporin 9 (AQP9) is a pore-forming transmembrane protein that facilitates hepatic uptake of glycerol. Its expression is inversely regulated by insulin in male rodents, with increased expression during fasting. Previous results indicate that PPARα plays a crucial role in the induction of AQP9 mRNA during fasting. In the present study, we use PPARα agonists to explore the effect of PPARα activation on hepatic AQP9 expression and on the abundance of enzymes involved in glycerol metabolism using both in vivo and in vitro systems. In male rats with free access to food, treatment with the PPARα agonist WY 14643 (3 mg·kg(-1)·day(-1)) caused a 50% reduction in hepatic AQP9 abundance with the effect being restricted to AQP9 expressed in periportal hepatocytes. The pharmacological activation of PPARα had no effect on the abundance of GlyK, whereas it caused an increased expression of hepatic GPD1, GPAT1, and L-FABP protein. In WIF-B9 and HepG2 hepatocytes, both WY 14643 and another PPARα agonist GW 7647 reduced the abundance of AQP9 protein. In conclusion, pharmacological PPARα activation results in a marked reduction in the abundance of AQP9 in periportal hepatocytes. Together with the effect on the enzymatic apparatus for glycerol metabolism, our results suggest that PPARα activation in the fed state directs glycerol into glycerolipid synthesis rather than into de novo synthesis of glucose.
过氧化物酶体增殖物激活受体 α（PPARα）是禁食状态下肝脏反应的关键调节因子，对脂质和碳水化合物代谢均有影响。也发现其在肝脏甘油代谢中具有作用；然而，结果有些矛盾。水通道蛋白 9（AQP9）是一种形成孔的跨膜蛋白，有助于肝脏摄取甘油。其在雄性啮齿动物中的表达受胰岛素的负调控，在禁食期间表达增加。先前的结果表明，PPARα 在禁食期间诱导 AQP9 mRNA 的表达中起关键作用。在本研究中，我们使用 PPARα 激动剂，在体内和体外系统中，探讨 PPARα 激活对肝 AQP9 表达和甘油代谢相关酶丰度的影响。在自由进食的雄性大鼠中，用 PPARα 激动剂 WY 14643（3mg·kg(-1)·day(-1)）处理会导致肝 AQP9 丰度降低 50%，其作用仅限于门脉周围肝细胞中表达的 AQP9。PPARα 的药理激活对 GlyK 的丰度没有影响，而导致肝 GPD1、GPAT1 和 L-FABP 蛋白表达增加。在 WIF-B9 和 HepG2 肝细胞中，WY 14643 和另一种 PPARα 激动剂 GW 7647 均可降低 AQP9 蛋白的丰度。总之，药理 PPARα 激活导致门脉周围肝细胞中 AQP9 的丰度明显降低。结合对甘油代谢酶装置的影响，我们的结果表明，在进食状态下，PPARα 的激活将甘油引导至甘油脂质合成，而不是引导至葡萄糖的从头合成。
