Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan.
Endocr J. 2010;57(4):317-24. doi: 10.1507/endocrj.k09e-298. Epub 2010 Feb 7.
Both glucocorticoid and insulin are known to have an anabolic effect on lipogenesis. Acetyl-CoA, an intermediate product of glycolysis, is supplied for fatty acid synthesis when carbohydrate intake is sufficient. Acetyl-CoA carboxylase (ACC), consisting of two isoenzymes ACC1 and ACC2, mediates the conversion from acetyl-CoA to malonyl-CoA, and thus plays a key role for the regulation of lipogenesis. In this study, we surveyed the effects of glucocorticoid and insulin on the transcriptional activity of the alternative promoters of ACCs (PI-PIII for ACC1, and PI and PII for ACC2) using the HepG2 human hepatocyte cell line in vitro. We also examined the roles of the insulin and/or glucose-regulated transcriptional factor(s) such as SREBP1c, LXRalpha/beta, and ChREBP on each promoter of the ACC genes. We found that both insulin and glucocorticoid had potent positive effects on all the promoters examined, and additive effects of both hormones were recognized in ACC1 PI and ACC2 PI. Furthermore, a representative insulin-responsive transcription factor SREBP1c showed significant stimulatory effects on all the promoters of ACC genes, among which those on ACC1 PIII and ACC2 PI were most prominent. On the other hand, the effect of LXRalpha was rather selective; it showed a marked stimulatory effect only on ACC1 PII. LXRbeta and ChREBP had minimal, if any, effects on some of the promoters. Altogether, our data suggest that insulin and glucocorticoid have positive effects on both ACC1 and ACC2 gene transcription. SREBP1c might be a master regulator of the expression of both genes regardless of the promoter utilized, whereas LXRalpha seems to play a promoter-specific role. Since ACC1 facilitates lipogenesis by stimulating fatty acid synthesis and ACC2 inhibits lipolysis, both insulin and glucocorticoid seem to play an important role in the pathogenesis of obesity and/or hepatic steatosis.
糖皮质激素和胰岛素都已知对脂肪生成具有合成代谢作用。当碳水化合物摄入充足时，糖酵解的中间产物乙酰辅酶 A 被供应用于脂肪酸合成。乙酰辅酶 A 羧化酶 (ACC) 由两种同工酶 ACC1 和 ACC2 组成，介导乙酰辅酶 A 向丙二酰辅酶 A 的转化，因此在脂肪生成的调节中发挥关键作用。在这项研究中，我们使用体外 HepG2 人肝细胞系调查了糖皮质激素和胰岛素对 ACC 同工酶（ACC1 的 PI-PIII 和 ACC2 的 PI 和 PII）的替代启动子的转录活性的影响。我们还检查了胰岛素和/或葡萄糖调节转录因子（如 SREBP1c、LXRalpha/beta 和 ChREBP）在 ACC 基因的每个启动子上的作用。我们发现，胰岛素和糖皮质激素对所有检测到的启动子都有强烈的正向作用，并且两种激素在 ACC1 PI 和 ACC2 PI 上具有加性作用。此外，一种有代表性的胰岛素反应性转录因子 SREBP1c 对 ACC 基因的所有启动子都表现出显著的刺激作用，其中对 ACC1 PIII 和 ACC2 PI 的刺激作用最为明显。另一方面，LXRalpha 的作用相当具有选择性；它仅对 ACC1 PII 表现出显著的刺激作用。LXRbeta 和 ChREBP 对一些启动子几乎没有影响。总之，我们的数据表明胰岛素和糖皮质激素对 ACC1 和 ACC2 基因的转录都有正向作用。SREBP1c 可能是两个基因表达的主调节因子，无论使用何种启动子，而 LXRalpha 似乎发挥启动子特异性作用。由于 ACC1 通过刺激脂肪酸合成促进脂肪生成，而 ACC2 抑制脂肪分解，因此胰岛素和糖皮质激素似乎在肥胖症和/或脂肪肝的发病机制中发挥重要作用。
