Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Cell Metab. 2024 Mar 5;36(3):617-629.e7. doi: 10.1016/j.cmet.2024.01.011. Epub 2024 Feb 9.
Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride (TG) synthesis. DGAT2 deletion in mice lowers liver TGs, and DGAT2 inhibitors are under investigation for the treatment of fatty liver disease. Here, we show that DGAT2 inhibition also suppressed SREBP-1 cleavage, reduced fatty acid synthesis, and lowered TG accumulation and secretion from liver. DGAT2 inhibition increased phosphatidylethanolamine (PE) levels in the endoplasmic reticulum (ER) and inhibited SREBP-1 cleavage, while DGAT2 overexpression lowered ER PE concentrations and increased SREBP-1 cleavage in vivo. ER enrichment with PE blocked SREBP-1 cleavage independent of Insigs, which are ER proteins that normally retain SREBPs in the ER. Thus, inhibition of DGAT2 shunted diacylglycerol into phospholipid synthesis, increasing the PE content of the ER, resulting in reduced SREBP-1 cleavage and less hepatic steatosis. This study reveals a new mechanism that regulates SREBP-1 activation and lipogenesis that is independent of sterols and SREBP-2 in liver.
二酰基甘油酰基转移酶 2（DGAT2）催化甘油三酯（TG）合成的最后一步。在小鼠中敲除 DGAT2 可降低肝脏中的 TG，DGAT2 抑制剂正在被研究用于治疗脂肪肝疾病。在这里，我们表明 DGAT2 抑制还抑制了 SREBP-1 的切割，减少了脂肪酸的合成，并降低了肝脏中 TG 的积累和分泌。DGAT2 抑制在线粒体中增加了磷酸乙醇胺（PE）的水平并抑制了 SREBP-1 的切割，而 DGAT2 的过表达降低了体内 ER 中的 PE 浓度并增加了 SREBP-1 的切割。用 PE 对 ER 进行富集可独立于 Insigs 阻断 SREBP-1 的切割，Insigs 是通常将 SREBPs 保留在线粒体中的内质网蛋白。因此，DGAT2 的抑制将二酰基甘油转移到磷脂合成中，增加了 ER 中的 PE 含量，从而减少了 SREBP-1 的切割和肝脏脂肪变性。这项研究揭示了一种新的调节机制，该机制独立于肝脏中的固醇和 SREBP-2 来激活 SREBP-1 和脂肪生成。
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