Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
J Biol Chem. 2010 Mar 19;285(12):8880-6. doi: 10.1074/jbc.M109.077164. Epub 2010 Jan 21.
Prostaglandin (PG) F(2alpha) suppresses adipocyte differentiation by inhibiting the function of peroxisome proliferator-activated receptor gamma. However, PGF(2alpha) synthase (PGFS) in adipocytes remains to be identified. Here, we studied the expression of members of the aldo-keto reductase (AKR) 1B family acting as PGFS during adipogenesis of mouse 3T3-L1 cells. AKR1B3 mRNA was expressed in preadipocytes, and its level increased about 4-fold at day 1 after initiation of adipocyte differentiation, and then quickly decreased the following day to a level lower than that in the preadipocytes. In contrast, the mRNA levels of Akr1b8 and 1b10 were clearly lower than that level of Akr1b3 in preadipocytes and remained unchanged during adipogenesis. The transient increase in Akr1b3 during adipogenesis was also observed by Western blot analysis. The mRNA for the FP receptor, which is selective for PGF(2alpha), was also expressed in preadipocytes. Its level increased about 2-fold within 1 h after the initiation of adipocyte differentiation and was maintained at almost the same level throughout adipocyte differentiation. The small interfering RNA for Akr1b3, but not for Akr1b8 or 1b10, suppressed PGF(2alpha) production and enhanced the expression of adipogenic genes such as peroxisome proliferator-activated receptor gamma, fatty acid-binding protein 4 (aP2), and stearoyl-CoA desaturase. Moreover, an FP receptor agonist, Fluprostenol, suppressed the expression of those adipogenic genes in 3T3-L1 cells; whereas an FP receptor antagonist, AL-8810, efficiently inhibited the suppression of adipogenesis caused by the endogenous PGF(2alpha). These results indicate that AKR1B3 acts as the PGFS in adipocytes and that AKR1B3-produced PGF(2alpha) suppressed adipocyte differentiation by acting through FP receptors.
前列腺素 (PG) F(2alpha) 通过抑制过氧化物酶体增殖物激活受体 γ 的功能来抑制脂肪细胞分化。然而，脂肪细胞中的前列腺素 F(2alpha) 合酶 (PGFS) 仍有待确定。在这里，我们研究了在小鼠 3T3-L1 细胞脂肪生成过程中作为 PGFS 发挥作用的醛酮还原酶 (AKR) 1B 家族成员的表达。AKR1B3 mRNA 在前脂肪细胞中表达，其水平在脂肪细胞分化开始后第 1 天增加约 4 倍，然后第二天迅速下降至低于前脂肪细胞的水平。相比之下，Akr1b8 和 1b10 的 mRNA 水平在前脂肪细胞中明显低于 Akr1b3 的水平，并且在脂肪生成过程中保持不变。通过 Western blot 分析也观察到 Akr1b3 在脂肪生成过程中的短暂增加。FP 受体的 mRNA，其对 PGF(2alpha) 具有选择性，在前脂肪细胞中也有表达。其水平在脂肪细胞分化开始后 1 小时内增加约 2 倍，并在整个脂肪细胞分化过程中保持几乎相同的水平。Akr1b3 的小干扰 RNA，但不是 Akr1b8 或 1b10，抑制 PGF(2alpha) 的产生并增强脂肪生成基因如过氧化物酶体增殖物激活受体 γ、脂肪酸结合蛋白 4 (aP2) 和硬脂酰辅酶 A 去饱和酶的表达。此外，FP 受体激动剂 Fluprostenol 抑制 3T3-L1 细胞中这些脂肪生成基因的表达；而 FP 受体拮抗剂 AL-8810 则有效地抑制了内源性 PGF(2alpha) 引起的脂肪生成抑制作用。这些结果表明，AKR1B3 作为 PGFS 在脂肪细胞中发挥作用，并且 AKR1B3 产生的 PGF(2alpha) 通过作用于 FP 受体来抑制脂肪细胞分化。
