Department of Pharmaceutical Sciences, Università del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy.
Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale (UPO), Via Solaroli 17, 28100 Novara, Italy.
Nutrients. 2024 Sep 26;16(19):3260. doi: 10.3390/nu16193260.
BACKGROUND/OBJECTIVES: Methyltransferase EZH2-mediated H3K27me3 is involved in liver inflammation and fibrosis, but its role in hepatic metabolic derangements is not yet clearly defined. We investigated if a high-fat diet (HFD) induced early changes in EZH2 expression and H3K27 me3 in the liver of mice.
Five-week-old mice were fed an HFD or a low-fat diet (Control) for 2 weeks (2 W) or 8 weeks (8 W). Body weight was recorded weekly. Glycemia and oral glucose tolerance were assessed at baseline and after 2 W-8 W. Finally, livers were collected for further analysis.
As expected, mice that received 8 W HFD showed an increase in body weight, glycemia, and liver steatosis and an impairment in glucose tolerance; no alterations were observed in 2 W HFD mice. Eight weeks of HFD caused hepatic EZH2 nuclear localization and increased H3 K27me3; surprisingly, the same alterations occurred in 2 W HFD mice livers, even before overweight onset. We demonstrated that selective EZH2 inhibition reduced H3K27me3 and counteracted lipid accumulation in HUH-7 cells upon palmitic acid treatment.
In conclusion, we point to EZH2/H3K27me3 as an early epigenetic event occurring in fatty-acid-challenged livers both in vivo and in vitro, thus establishing EZH2 as a potential pharmacological target for metabolic derangements.
背景/目的：甲基转移酶 EZH2 介导的 H3K27me3 参与肝脏炎症和纤维化，但它在肝代谢紊乱中的作用尚不清楚。我们研究了高脂肪饮食（HFD）是否会引起小鼠肝脏中 EZH2 表达和 H3K27me3 的早期变化。
5 周龄的小鼠接受 HFD 或低脂饮食（对照）喂养 2 周（2 W）或 8 周（8 W）。每周记录体重。在基线和 2 W-8 W 后评估血糖和口服葡萄糖耐量。最后，收集肝脏进行进一步分析。
正如预期的那样，接受 8 W HFD 的小鼠体重增加、血糖升高、肝脂肪变性和葡萄糖耐量受损；2 W HFD 小鼠未观察到改变。8 周的 HFD 导致肝脏 EZH2 核定位和 H3 K27me3 增加；令人惊讶的是，2 W HFD 小鼠肝脏也发生了同样的改变，甚至在超重发生之前。我们证明，选择性 EZH2 抑制可减少 HUH-7 细胞中棕榈酸处理时的 H3K27me3，并拮抗脂质积累。
总之，我们指出 EZH2/H3K27me3 是脂肪酸挑战的肝脏中发生的早期表观遗传事件，无论是在体内还是在体外，从而确立 EZH2 作为代谢紊乱的潜在药物靶点。
