{"title":"羧基酯脂肪酶通过与脂肪酸合成酶结合防止代谢功能障碍相关性脂肪性肝炎","authors":"","doi":"10.1016/j.eng.2024.04.018","DOIUrl":null,"url":null,"abstract":"<div><div>Carboxyl ester lipase (CEL), a pivotal enzyme involved in lipid metabolism, is recurrently mutated in obese mice. Here, we aimed to elucidate the functional significance, molecular mechanism, and therapeutic potential of CEL in metabolic dysfunction-associated steatohepatitis (MASH). Hepatocyte-specific carboxyl ester lipase gene (<em>Cel</em>) knockout (<em>Cel</em><sup>ΔHEP</sup>) and wildtype (WT) littermates were fed with choline-deficient high-fat diet (CD-HFD) for 16 weeks, or methionine- and choline-deficient diet (MCD) for three weeks to induce MASH. Liquid chromatography–mass spectrometry and co-immunoprecipitation were employed to identify the downstream targets of CEL. CD-HFD/MCD-fed WT mice received intravenous injections of CEL-adeno-associated viral, serotype 8 (AAV8) to induce specific overexpression of CEL in the liver. We observed a decrease in CEL protein levels in MASH induced by CD-HFD or MCD in mice. <em>Cel</em><sup>ΔHEP</sup> mice fed with CD-HFD or MCD exhibited pronounced hepatic steatosis, inflammation, lipid peroxidation, and liver injury compared to WT littermates, accompanied by increased hepatic nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation. Consistently, <em>Cel</em> knockdown in mouse primary hepatocytes and AML12 cells aggravated lipid accumulation and inflammation, whereas CEL overexpression exerted the opposite effect. Mechanistically, CEL directly bound to fatty acid synthase (FASN), resulting in reduced FASN SUMOylation, which in turn promoted FASN degradation through the proteasome pathway. Furthermore, inhibition of FASN ameliorated hepatocyte lipid accumulation and inflammation induced by <em>Cel</em> knockdown <em>in vivo</em> and <em>in vitro</em>. Hepatocyte-specific CEL overexpression using AAV8-<em>Cel</em> significantly mitigated steatohepatitis in mice fed with CD-HFD or MCD. CEL protects against steatohepatitis development by directly interacting with FASN and suppressing its expression for <em>de novo</em> lipogenesis. CEL overexpression confers a therapeutic benefit in steatohepatitis.</div></div>","PeriodicalId":11783,"journal":{"name":"Engineering","volume":null,"pages":null},"PeriodicalIF":10.1000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Carboxyl Ester Lipase Protects Against Metabolic Dysfunction-Associated Steatohepatitis by Binding to Fatty Acid Synthase\",\"authors\":\"\",\"doi\":\"10.1016/j.eng.2024.04.018\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Carboxyl ester lipase (CEL), a pivotal enzyme involved in lipid metabolism, is recurrently mutated in obese mice. Here, we aimed to elucidate the functional significance, molecular mechanism, and therapeutic potential of CEL in metabolic dysfunction-associated steatohepatitis (MASH). Hepatocyte-specific carboxyl ester lipase gene (<em>Cel</em>) knockout (<em>Cel</em><sup>ΔHEP</sup>) and wildtype (WT) littermates were fed with choline-deficient high-fat diet (CD-HFD) for 16 weeks, or methionine- and choline-deficient diet (MCD) for three weeks to induce MASH. Liquid chromatography–mass spectrometry and co-immunoprecipitation were employed to identify the downstream targets of CEL. CD-HFD/MCD-fed WT mice received intravenous injections of CEL-adeno-associated viral, serotype 8 (AAV8) to induce specific overexpression of CEL in the liver. We observed a decrease in CEL protein levels in MASH induced by CD-HFD or MCD in mice. <em>Cel</em><sup>ΔHEP</sup> mice fed with CD-HFD or MCD exhibited pronounced hepatic steatosis, inflammation, lipid peroxidation, and liver injury compared to WT littermates, accompanied by increased hepatic nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation. Consistently, <em>Cel</em> knockdown in mouse primary hepatocytes and AML12 cells aggravated lipid accumulation and inflammation, whereas CEL overexpression exerted the opposite effect. Mechanistically, CEL directly bound to fatty acid synthase (FASN), resulting in reduced FASN SUMOylation, which in turn promoted FASN degradation through the proteasome pathway. Furthermore, inhibition of FASN ameliorated hepatocyte lipid accumulation and inflammation induced by <em>Cel</em> knockdown <em>in vivo</em> and <em>in vitro</em>. Hepatocyte-specific CEL overexpression using AAV8-<em>Cel</em> significantly mitigated steatohepatitis in mice fed with CD-HFD or MCD. CEL protects against steatohepatitis development by directly interacting with FASN and suppressing its expression for <em>de novo</em> lipogenesis. CEL overexpression confers a therapeutic benefit in steatohepatitis.</div></div>\",\"PeriodicalId\":11783,\"journal\":{\"name\":\"Engineering\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":10.1000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Engineering\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2095809924002546\",\"RegionNum\":1,\"RegionCategory\":\"工程技术\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENGINEERING, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Engineering","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2095809924002546","RegionNum":1,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
摘要
羧基酯脂肪酶(CEL)是一种参与脂质代谢的关键酶,在肥胖小鼠中反复发生突变。在此,我们旨在阐明 CEL 在代谢功能障碍相关性脂肪性肝炎(MASH)中的功能意义、分子机制和治疗潜力。用胆碱缺乏的高脂饮食(CD-HFD)或蛋氨酸和胆碱缺乏的饮食(MCD)喂养肝细胞特异性羧基酯脂肪酶基因(Cel)敲除(CelΔHEP)和野生型(WT)小鼠16周,以诱导MASH。研究人员采用液相色谱-质谱法和共免疫沉淀法来确定CEL的下游靶标。CD-HFD/MCD 喂养的 WT 小鼠静脉注射 CEL 腺相关病毒血清型 8(AAV8)以诱导 CEL 在肝脏中特异性过表达。我们观察到,在 CD-HFD 或 MCD 诱导的小鼠 MASH 中,CEL 蛋白水平有所下降。与 WT 小鼠相比,用 CD-HFD 或 MCD 喂养的 CelΔHEP 小鼠表现出明显的肝脏脂肪变性、炎症、脂质过氧化和肝损伤,同时伴有肝脏核因子卡巴轻链-活化 B 细胞增强子(NF-κB)激活增加。同样,在小鼠原代肝细胞和 AML12 细胞中敲除 Cel 会加剧脂质积累和炎症,而过表达 CEL 则会产生相反的效果。从机理上讲,CEL 直接与脂肪酸合成酶(FASN)结合,导致 FASN SUMOylation 减少,进而促进 FASN 通过蛋白酶体途径降解。此外,抑制 FASN 可改善 Cel 敲除在体内和体外诱导的肝细胞脂质积累和炎症。使用AAV8-Cel过表达肝细胞特异性CEL可显著减轻以CD-HFD或MCD喂养的小鼠的脂肪性肝炎。CEL 通过直接与 FASN 相互作用并抑制其表达以促进脂肪的新生,从而防止脂肪性肝炎的发生。CEL 的过表达对脂肪性肝炎有治疗作用。
Carboxyl Ester Lipase Protects Against Metabolic Dysfunction-Associated Steatohepatitis by Binding to Fatty Acid Synthase
Carboxyl ester lipase (CEL), a pivotal enzyme involved in lipid metabolism, is recurrently mutated in obese mice. Here, we aimed to elucidate the functional significance, molecular mechanism, and therapeutic potential of CEL in metabolic dysfunction-associated steatohepatitis (MASH). Hepatocyte-specific carboxyl ester lipase gene (Cel) knockout (CelΔHEP) and wildtype (WT) littermates were fed with choline-deficient high-fat diet (CD-HFD) for 16 weeks, or methionine- and choline-deficient diet (MCD) for three weeks to induce MASH. Liquid chromatography–mass spectrometry and co-immunoprecipitation were employed to identify the downstream targets of CEL. CD-HFD/MCD-fed WT mice received intravenous injections of CEL-adeno-associated viral, serotype 8 (AAV8) to induce specific overexpression of CEL in the liver. We observed a decrease in CEL protein levels in MASH induced by CD-HFD or MCD in mice. CelΔHEP mice fed with CD-HFD or MCD exhibited pronounced hepatic steatosis, inflammation, lipid peroxidation, and liver injury compared to WT littermates, accompanied by increased hepatic nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation. Consistently, Cel knockdown in mouse primary hepatocytes and AML12 cells aggravated lipid accumulation and inflammation, whereas CEL overexpression exerted the opposite effect. Mechanistically, CEL directly bound to fatty acid synthase (FASN), resulting in reduced FASN SUMOylation, which in turn promoted FASN degradation through the proteasome pathway. Furthermore, inhibition of FASN ameliorated hepatocyte lipid accumulation and inflammation induced by Cel knockdown in vivo and in vitro. Hepatocyte-specific CEL overexpression using AAV8-Cel significantly mitigated steatohepatitis in mice fed with CD-HFD or MCD. CEL protects against steatohepatitis development by directly interacting with FASN and suppressing its expression for de novo lipogenesis. CEL overexpression confers a therapeutic benefit in steatohepatitis.
期刊介绍:
Engineering, an international open-access journal initiated by the Chinese Academy of Engineering (CAE) in 2015, serves as a distinguished platform for disseminating cutting-edge advancements in engineering R&D, sharing major research outputs, and highlighting key achievements worldwide. The journal's objectives encompass reporting progress in engineering science, fostering discussions on hot topics, addressing areas of interest, challenges, and prospects in engineering development, while considering human and environmental well-being and ethics in engineering. It aims to inspire breakthroughs and innovations with profound economic and social significance, propelling them to advanced international standards and transforming them into a new productive force. Ultimately, this endeavor seeks to bring about positive changes globally, benefit humanity, and shape a new future.