Zbtb7c is a proto-oncoprotein that controls the cell cycle and glucose, glutamate, and lipid metabolism. Zbtb7c expression is increased in the liver and white adipose tissues of aging or high-fat diet-fed mice. Knockout or knockdown of Zbtb7c gene expression inhibits the adipocyte differentiation of 3T3-L1 cells and decreases adipose tissue mass in aging mice. We found that Zbtb7c was a potent transcriptional repressor of SIRT1 and that SIRT1 was derepressed in various tissues of Zbtb7c-KO mice. Mechanistically, Zbtb7c interacted with p53 and bound to the proximal promoter p53RE1 and p53RE2 to repress the SIRT1 gene, in which p53RE2 was particularly critical. Zbtb7c induced p53 to interact with the corepressor mSin3A-HADC1 complex at p53RE. By repressing the SIRT1 gene, Zbtb7c increased the acetylation of Pgc-1α and Pparγ, which resulted in repression or activation of Pgc-1α or Pparγ target genes involved in lipid metabolism. Our study provides a molecular target that can overexpress SIRT1 protein in the liver, pancreas, and adipose tissues, which can be beneficial in the treatment of diabetes, obesity, longevity, etc.

Zbtb7c 是一种原癌蛋白，可控制细胞周期和葡萄糖、谷氨酸和脂质代谢。Zbtb7c 在衰老或高脂饮食喂养小鼠的肝脏和白色脂肪组织中的表达增加。敲除或敲除 Zbtb7c 基因表达可抑制 3T3-L1 细胞的脂肪细胞分化并减少衰老小鼠的脂肪组织质量。我们发现 Zbtb7c 是SIRT1的有效转录抑制因子，并且SIRT1在Zbtb7c -KO 小鼠的各种组织中被解除抑制。从机制上讲，Zbtb7c 与 p53 相互作用并与近端启动子 p53RE1 和 p53RE2 结合以抑制SIRT1基因，其中 p53RE2 尤为关键。Zbtb7c 诱导 p53 在 p53RE 与辅阻遏物 mSin3A-HADC1 复合物相互作用。通过抑制SIRT1基因，Zbtb7c 增加了 Pgc-1α 和 Pparγ 的乙酰化，从而导致参与脂质代谢的 Pgc-1α 或 Pparγ 靶基因的抑制或激活。我们的研究提供了一个分子靶点，可以在肝脏、胰腺和脂肪组织中过表达 SIRT1 蛋白，这对治疗糖尿病、肥胖、长寿等有益。