Stapleton S R, Mitchell D A, Salati L M, Goodridge A G
Department of Biochemistry, School of Medicine, University of Iowa, Iowa City 52242.
J Biol Chem. 1990 Oct 25;265(30):18442-6.
Hepatic fatty acid synthase is regulated by nutritional state. Starvation decreases and refeeding increases the activity of avian fatty acid synthase, principally by regulating transcription of the gene (Back, B. W., Goldman, M. J., Fisch, J.E., Ochs, R.A., and Goodridge, A.G. (1986) J. Biol. Chem. 261, 4190-4197). In chick embryo hepatocytes in culture, the stimulatory effect of feeding on fatty acid synthase activity is mimicked by adding triiodothyronine and insulin; the inhibitory effect of starvation is mimicked by adding glucagon or cyclic AMP. We now show that triiodothyronine alone stimulates transcription of fatty acid synthase by 4- to 6-fold, about the same as the increase in fatty acid synthase mRNA. When added alone, insulin has little or no effect on transcription, mRNA level, or enzyme activity. In combination with triiodothyronine, however, insulin amplifies the response to triiodothyronine by about 2-fold, leading to an overall increase of about 10-fold. Insulin-like growth factor 1 (IGF-1) has the same effect as insulin, no effect by itself, and amplification of the stimulation by triiodothyronine. A maximally effective dose of insulin has no effect in the presence of a maximally effective dose of IGF-1, suggesting regulation by a common pathway. It takes much less IGF-1 than insulin to achieve a given effect, suggesting that both insulin and IGF-1 may act through IGF-1 receptors. Plasma levels of IGF-1 are decreased by starvation and increased by feeding (reviewed by Froesch, E.R., and Zapf, J. (1985) Diabetologia 28, 485-493). Thus, IGF-1 may play a physiological role in the regulation of hepatic fatty acid synthase during transitions between the starved and fed states, roles previously assigned primarily to insulin and glucagon. IGF-1 regulates transcription of the fatty acid synthase gene. Insulin and IGF-1 also have similar effects on activity, mRNA abundance, and transcription of the malic enzyme gene. Glucagon or dibutyryl cyclic AMP inhibit fatty acid synthase activity and mRNA level in hepatocytes in culture by 70-80% and 60%, respectively, but have no effect on transcription of the fatty acid synthase gene, suggesting a post-transcriptional mode of regulation for cyclic AMP.
肝脏脂肪酸合酶受营养状态的调节。饥饿会降低禽类脂肪酸合酶的活性，而再喂食则会增加其活性，主要是通过调节该基因的转录（Back, B. W., Goldman, M. J., Fisch, J.E., Ochs, R.A., and Goodridge, A.G. (1986) J. Biol. Chem. 261, 4190 - 4197）。在培养的鸡胚肝细胞中，添加三碘甲状腺原氨酸和胰岛素可模拟喂食对脂肪酸合酶活性的刺激作用；添加胰高血糖素或环磷酸腺苷可模拟饥饿的抑制作用。我们现在表明，单独的三碘甲状腺原氨酸可将脂肪酸合酶的转录刺激4至6倍，与脂肪酸合酶mRNA的增加幅度大致相同。单独添加时，胰岛素对转录、mRNA水平或酶活性几乎没有影响。然而，与三碘甲状腺原氨酸联合使用时，胰岛素可将对三碘甲状腺原氨酸的反应放大约2倍，导致总体增加约10倍。胰岛素样生长因子1（IGF - 1）与胰岛素具有相同的作用，自身无作用，但可放大三碘甲状腺原氨酸的刺激作用。在最大有效剂量的IGF - 1存在时，最大有效剂量的胰岛素无作用，这表明它们通过共同途径进行调节。达到给定效果所需的IGF - 1比胰岛素少得多，这表明胰岛素和IGF - 1可能都通过IGF - 1受体发挥作用。饥饿会降低血浆IGF - 1水平，喂食则会使其升高（Froesch, E.R., and Zapf, J. (1985) Diabetologia 28, 485 - 493综述）。因此，在饥饿和喂食状态之间的转变过程中，IGF - 1可能在肝脏脂肪酸合酶的调节中发挥生理作用，而之前这些作用主要归因于胰岛素和胰高血糖素。IGF - 1调节脂肪酸合酶基因的转录。胰岛素和IGF - 1对苹果酸酶基因的活性、mRNA丰度和转录也有类似的作用。胰高血糖素或二丁酰环磷酸腺苷分别使培养的肝细胞中脂肪酸合酶活性和mRNA水平降低70 - 80%和60%，但对脂肪酸合酶基因的转录没有影响，这表明环磷酸腺苷的调节方式为转录后调节。
