Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
J Clin Invest. 2020 Jun 1;130(6):2992-3004. doi: 10.1172/JCI128073.
De novo lipogenesis is tightly regulated by insulin and nutritional signals to maintain metabolic homeostasis. Excessive lipogenesis induces lipotoxicity, leading to nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Genetic lipogenic programs have been extensively investigated, but epigenetic regulation of lipogenesis is poorly understood. Here, we identified Slug as an important epigenetic regulator of lipogenesis. Hepatic Slug levels were markedly upregulated in mice by either feeding or insulin treatment. In primary hepatocytes, insulin stimulation increased Slug expression, stability, and interactions with epigenetic enzyme lysine-specific demethylase-1 (Lsd1). Slug bound to the fatty acid synthase (Fasn) promoter where Slug-associated Lsd1 catalyzed H3K9 demethylation, thereby stimulating Fasn expression and lipogenesis. Ablation of Slug blunted insulin-stimulated lipogenesis. Conversely, overexpression of Slug, but not a Lsd1 binding-defective Slug mutant, stimulated Fasn expression and lipogenesis. Lsd1 inhibitor treatment also blocked Slug-stimulated lipogenesis. Remarkably, hepatocyte-specific deletion of Slug inhibited the hepatic lipogenic program and protected against obesity-associated NAFLD, insulin resistance, and glucose intolerance in mice. Conversely, liver-restricted overexpression of Slug, but not the Lsd1 binding-defective Slug mutant, had the opposite effects. These results unveil an insulin/Slug/Lsd1/H3K9 demethylation lipogenic pathway that promotes NAFLD and type 2 diabetes.
从头合成脂是受胰岛素和营养信号的严格调节，以维持代谢平衡。过度的从头合成脂会引起脂毒性，导致非酒精性脂肪性肝病（NAFLD）和 2 型糖尿病。遗传的脂生成程序已经得到了广泛的研究，但脂生成的表观遗传调控知之甚少。在这里，我们发现 Slug 是脂生成的一个重要的表观遗传调控因子。无论是通过喂养还是胰岛素处理，小鼠肝脏中的 Slug 水平都明显上调。在原代肝细胞中，胰岛素刺激增加了 Slug 的表达、稳定性和与表观遗传酶赖氨酸特异性去甲基化酶-1（Lsd1）的相互作用。Slug 结合到脂肪酸合成酶（Fasn）启动子上，Slug 相关的 Lsd1 在此处催化 H3K9 去甲基化，从而刺激 Fasn 的表达和脂生成。Slug 的缺失削弱了胰岛素刺激的脂生成。相反，Slug 的过表达，而不是 Lsd1 结合缺陷的 Slug 突变体，刺激 Fasn 的表达和脂生成。Lsd1 抑制剂治疗也阻断了 Slug 刺激的脂生成。值得注意的是，肝细胞特异性缺失 Slug 抑制了肝脂生成程序，并防止肥胖相关的 NAFLD、胰岛素抵抗和葡萄糖不耐受在小鼠中发生。相反，肝脏特异性过表达 Slug，而不是 Lsd1 结合缺陷的 Slug 突变体，产生了相反的效果。这些结果揭示了一个胰岛素/Slug/Lsd1/H3K9 去甲基化的脂生成途径，它促进了 NAFLD 和 2 型糖尿病的发生。
