Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nat Med. 2012 Jun;18(6):934-42. doi: 10.1038/nm.2744.
Fatty liver disease is associated with obesity and type 2 diabetes, and hepatic lipid accumulation may contribute to insulin resistance. Histone deacetylase 3 (Hdac3) controls the circadian rhythm of hepatic lipogenesis. Here we show that, despite severe hepatosteatosis, mice with liver-specific depletion of Hdac3 have higher insulin sensitivity without any changes in insulin signaling or body weight compared to wild-type mice. Hdac3 depletion reroutes metabolic precursors towards lipid synthesis and storage within lipid droplets and away from hepatic glucose production. Perilipin 2, which coats lipid droplets, is markedly induced upon Hdac3 depletion and contributes to the development of both steatosis and improved tolerance to glucose. These findings suggest that the sequestration of hepatic lipids in perilipin 2–coated droplets ameliorates insulin resistance and establish Hdac3 as a pivotal epigenomic modifier that integrates signals from the circadian clock in the regulation of hepatic intermediary metabolism.
脂肪肝疾病与肥胖症和 2 型糖尿病有关，肝脏脂质堆积可能导致胰岛素抵抗。组蛋白去乙酰化酶 3（Hdac3）控制肝脏脂肪生成的昼夜节律。在这里，我们发现尽管存在严重的肝脂肪变性，但与野生型小鼠相比，肝脏特异性缺失 Hdac3 的小鼠具有更高的胰岛素敏感性，而胰岛素信号或体重没有任何变化。Hdac3 的缺失将代谢前体重新引导到脂质合成和储存到脂滴中，并远离肝脏葡萄糖生成。包裹脂滴的 perilipin 2 在 Hdac3 缺失时明显诱导，并有助于脂肪变性的发展和对葡萄糖的耐受性提高。这些发现表明，perilipin 2 包裹的脂滴中肝脏脂质的隔离改善了胰岛素抵抗，并确定 Hdac3 是一种关键的表观遗传修饰因子，它整合了生物钟的信号，调节肝脏中间代谢。
