DGAT2 inhibition blocks SREBP-1 cleavage and improves hepatic steatosis by increasing phosphatidylethanolamine in the ER.

Cell metabolism Pub Date : 2024-03-05 Epub Date: 2024-02-09 DOI:10.1016/j.cmet.2024.01.011
Shunxing Rong, Mingfeng Xia, Goncalo Vale, Simeng Wang, Chai-Wan Kim, Shili Li, Jeffrey G McDonald, Arun Radhakrishnan, Jay D Horton
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Abstract

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.

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抑制 DGAT2 可阻止 SREBP-1 的裂解,并通过增加 ER 中的磷脂酰乙醇胺来改善肝脏脂肪变性。
二酰甘油酰基转移酶 2(DGAT2)催化甘油三酯(TG)合成的最后一步。小鼠体内的 DGAT2 基因缺失会降低肝脏中的 TG,目前正在研究 DGAT2 抑制剂用于治疗脂肪肝。在这里,我们发现抑制 DGAT2 还能抑制 SREBP-1 的裂解,减少脂肪酸的合成,降低肝脏中 TG 的积累和分泌。抑制DGAT2会增加内质网(ER)中磷脂酰乙醇胺(PE)的含量并抑制SREBP-1的裂解,而过表达DGAT2会降低ER中PE的浓度并增加体内SREBP-1的裂解。用PE富集ER可阻止SREBP-1的裂解,而与Insigs无关,Insigs是通常将SREBPs保留在ER中的ER蛋白。因此,抑制 DGAT2 可将二酰甘油分流到磷脂合成中,增加 ER 中的 PE 含量,从而减少 SREBP-1 的裂解,减轻肝脏脂肪变性。这项研究揭示了一种调节 SREBP-1 激活和脂肪生成的新机制,它与肝脏中的固醇和 SREBP-2 无关。
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