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ATGL是一种羟基脂肪酸的脂肪酸酯生物合成酶
2022-06-12 22:59

美国哈佛医学院Barbara B. Kahn课题组发现,ATGL是一种羟基脂肪酸的脂肪酸酯生物合成酶。这一研究成果于2022年6月8日在线发表在国际学术期刊《自然》上。

研究人员表示,羟基脂肪酸(HFA;FAHFA)的支链FA酯是最近发现的脂类,从酵母到哺乳动物都是保守的。一个亚家族,羟基硬脂酸的棕榈酸酯(PAHSA),具有抗炎和抗糖尿病的作用。有胰岛素抵抗的人类和小鼠皮下脂肪组织和血清中的PAHSA水平较低。给予PAHSA可以改善葡萄糖耐量和胰岛素敏感性,并减少肥胖症、糖尿病和免疫介导的疾病的炎症。负责体内FAHFA生物合成的酶仍然未知。

研究人员利用化学生物学和蛋白质组学确定了脂肪甘油三酯脂肪酶(ATGL,也被称为含有帕塔丁样磷脂酶域2(PNPLA2))作为FAHFA的候选生物合成酶。结果发现,重组ATGL使用一个反酰基反应,将HFA与来自甘油三酯(TG)或甘油二酯的FA进行酯化,从而产生FAHFA。过量表达野生型而不是没有催化作用的ATGL会增加FAHFA的生物合成。对ATGL的化学抑制或Atgl的基因缺失会抑制FAHFA的生物合成,并降低FAHFA和FAHFA-TG的水平。在特异性敲除Atgl的小鼠脂肪组织中,内源性和新生的FAHFA和FAHFA-TG的水平降低80-90%。

通过提高二酰基甘油转移酶(DGAT)的活性来增加TG的水平,可以促进FAHFA的生物合成,而降低DGAT的活性则会抑制它,加强TG作为FAHFA前体的作用。ATGL生物合成转酰基酶的活性存在于人类脂肪组织中,强调了其潜在的临床意义。总之,研究人员发现了第一个在哺乳动物中催化形成FAHFA酯键的生物合成酶。虽然ATGL脂肪酶的活性是众所周知的,但这些数据建立了一个范式的转变,表明ATGL转酰基酶的活性在生物学上是重要的。

附:英文原文

Title: ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids

Author: Patel, Rucha, Santoro, Anna, Hofer, Peter, Tan, Dan, Oberer, Monika, Nelson, Andrew T., Konduri, Srihari, Siegel, Dionicio, Zechner, Rudolf, Saghatelian, Alan, Kahn, Barbara B.

Issue&Volume: 2022-06-08

Abstract: Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals1,2. A subfamily, palmitic acid esters of hydroxy stearic acids (PAHSAs), are anti-inflammatory and anti-diabetic1,3. Humans and mice with insulin resistance have lower PAHSA levels in subcutaneous adipose tissue and serum1. PAHSA administration improves glucose tolerance and insulin sensitivity and reduces inflammation in obesity, diabetes and immune-mediated diseases1,4,5,6,7. The enzyme(s) responsible for FAHFA biosynthesis in vivo remains unknown. Here we identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2 (PNPLA2)) as a candidate biosynthetic enzyme for FAHFAs using chemical biology and proteomics. We discovered that recombinant ATGL uses a transacylation reaction that esterifies an HFA with a FA from triglyceride (TG) or diglyceride to produce FAHFAs. Overexpression of wild-type, but not catalytically dead, ATGL increases FAHFA biosynthesis. Chemical inhibition of ATGL or genetic deletion of Atgl inhibits FAHFA biosynthesis and reduces the levels of FAHFA and FAHFA-TG. Levels of endogenous and nascent FAHFAs and FAHFA-TGs are 80–90 per cent lower in adipose tissue of mice in which Atgl is knocked out specifically in the adipose tissue. Increasing TG levels by upregulating diacylglycerol acyltransferase (DGAT) activity promotes FAHFA biosynthesis, and decreasing DGAT activity inhibits it, reinforcing TGs as FAHFA precursors. ATGL biosynthetic transacylase activity is present in human adipose tissue underscoring its potential clinical relevance. In summary, we discovered the first, to our knowledge, biosynthetic enzyme that catalyses the formation of the FAHFA ester bond in mammals. Whereas ATGL lipase activity is well known, our data establish a paradigm shift demonstrating that ATGL transacylase activity is biologically important.

DOI: 10.1038/s41586-022-04787-x

Source: https://www.nature.com/articles/s41586-022-04787-x

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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