Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA; Department of Pharmacology and Toxicology, Pharmacy College, Taibah University, Medina, Saudi Arabia.
J Lipid Res. 2023 Sep;64(9):100361. doi: 10.1016/j.jlr.2023.100361. Epub 2023 Mar 22.
N-acyl taurines (NATs) are bioactive lipids with emerging roles in glucose homeostasis and lipid metabolism. The acyl chains of hepatic and biliary NATs are enriched in polyunsaturated fatty acids (PUFAs). Dietary supplementation with a class of PUFAs, the omega-3 fatty acids, increases their cognate NATs in mice and humans. However, the synthesis pathway of the PUFA-containing NATs remains undiscovered. Here, we report that human livers synthesize NATs and that the acyl-chain preference is similar in murine liver homogenates. In the mouse, we found that hepatic NAT synthase activity localizes to the peroxisome and depends upon an active-site cysteine. Using unbiased metabolomics and proteomics, we identified bile acid-CoA:amino acid N-acyltransferase (BAAT) as the likely hepatic NAT synthase in vitro. Subsequently, we confirmed that BAAT knockout livers lack up to 90% of NAT synthase activity and that biliary PUFA-containing NATs are significantly reduced compared with wildtype. In conclusion, we identified the in vivo PUFA-NAT synthase in the murine liver and expanded the known substrates of the bile acid-conjugating enzyme, BAAT, beyond classic bile acids to the synthesis of a novel class of bioactive lipids.
N-酰基牛磺酸 (NATs) 是一类具有生物活性的脂质，在葡萄糖稳态和脂质代谢中具有重要作用。肝和胆 NAT 的酰基链富含多不饱和脂肪酸 (PUFAs)。饮食补充一类 PUFAs，即 ω-3 脂肪酸，可增加其在小鼠和人类中的同源 NAT。然而，含有 PUFAs 的 NAT 的合成途径仍未被发现。在这里，我们报告人类肝脏合成 NAT，并且在鼠肝匀浆中具有相似的酰基链偏好。在小鼠中，我们发现肝 NAT 合酶活性定位于过氧化物酶体，并且依赖于活性位点半胱氨酸。使用无偏代谢组学和蛋白质组学，我们鉴定出胆酸-CoA：氨基酸 N-酰基转移酶 (BAAT) 可能是体内的 NAT 合酶。随后，我们证实 BAAT 敲除的肝脏缺乏高达 90%的 NAT 合酶活性，并且与野生型相比，胆汁中含有 PUFAs 的 NAT 明显减少。总之，我们鉴定出了鼠肝中内源性的 PUFAs-NAT 合酶，并扩展了胆汁酸结合酶 BAAT 的已知底物范围，除了经典的胆汁酸之外，还包括了一类新的生物活性脂质的合成。
