Fahad Farhan , Rakesh Kotapati Raghupathy , Michal R. Baran , Aileen Wong , Lincoln Biswas , Hui-Rong Jiang , John A. Craft , Xinhua Shu
{"title":"Tspo 基因敲除小鼠肝脏脂质代谢失调。","authors":"Fahad Farhan , Rakesh Kotapati Raghupathy , Michal R. Baran , Aileen Wong , Lincoln Biswas , Hui-Rong Jiang , John A. Craft , Xinhua Shu","doi":"10.1016/j.bbalip.2024.159566","DOIUrl":null,"url":null,"abstract":"<div><div>The translocator protein, TSPO, has been implicated in a wide range of cellular processes exerted from its position in the outer mitochondrial membrane from where it influences lipid metabolism and mitochondrial oxidative activity. Understanding how this protein regulates a profusion of processes requires further elucidation and to that end we have examined lipid metabolism and used an RNAseq strategy to compare transcript abundance in wildtype and <em>Tspo</em> knockout (KO) mouse liver. The levels of cholesterol, triglyceride and phospholipid were significantly elevated in the KO mouse liver. The expression of cholesterol homeostasis genes was markedly downregulated. Determination of the differential expression revealed that many genes were either up- or downregulated in the KO animals. However, a striking observation within the results was a decrease of transcripts for protein degradation proteins in KO animals while protease inhibitors were enriched. When the entire abundance data-set was analysed with CEMiTool, and revealed a module of proteins that were under-represented in the KO animals. These could subsequently be formed into a network comprising three interlinked clusters at the centre of which were proteins of cytoplasmic ribosomes with gene ontology terms suggesting impairment to translation. The largest cluster was dominated by proteins of lipid metabolism but also contained disparate systems of iron metabolism and behaviour. The third cluster was dominated by proteins of the electron transport chain and oxidative phosphorylation. These findings suggest that TSPO contributes to lipid metabolism, detoxification of active oxygen species and oxidative phosphorylation, and regulates mitochondrial retrograde signalling.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 1","pages":"Article 159566"},"PeriodicalIF":3.9000,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dysregulation of lipid metabolism in the liver of Tspo knockout mice\",\"authors\":\"Fahad Farhan , Rakesh Kotapati Raghupathy , Michal R. Baran , Aileen Wong , Lincoln Biswas , Hui-Rong Jiang , John A. Craft , Xinhua Shu\",\"doi\":\"10.1016/j.bbalip.2024.159566\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The translocator protein, TSPO, has been implicated in a wide range of cellular processes exerted from its position in the outer mitochondrial membrane from where it influences lipid metabolism and mitochondrial oxidative activity. Understanding how this protein regulates a profusion of processes requires further elucidation and to that end we have examined lipid metabolism and used an RNAseq strategy to compare transcript abundance in wildtype and <em>Tspo</em> knockout (KO) mouse liver. The levels of cholesterol, triglyceride and phospholipid were significantly elevated in the KO mouse liver. The expression of cholesterol homeostasis genes was markedly downregulated. Determination of the differential expression revealed that many genes were either up- or downregulated in the KO animals. However, a striking observation within the results was a decrease of transcripts for protein degradation proteins in KO animals while protease inhibitors were enriched. When the entire abundance data-set was analysed with CEMiTool, and revealed a module of proteins that were under-represented in the KO animals. These could subsequently be formed into a network comprising three interlinked clusters at the centre of which were proteins of cytoplasmic ribosomes with gene ontology terms suggesting impairment to translation. The largest cluster was dominated by proteins of lipid metabolism but also contained disparate systems of iron metabolism and behaviour. The third cluster was dominated by proteins of the electron transport chain and oxidative phosphorylation. These findings suggest that TSPO contributes to lipid metabolism, detoxification of active oxygen species and oxidative phosphorylation, and regulates mitochondrial retrograde signalling.</div></div>\",\"PeriodicalId\":8815,\"journal\":{\"name\":\"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\"volume\":\"1870 1\",\"pages\":\"Article 159566\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2024-09-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1388198124001161\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochimica et biophysica acta. Molecular and cell biology of lipids","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1388198124001161","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
转运蛋白 TSPO 位于线粒体外膜,影响着线粒体的脂质代谢和氧化活性,因此与多种细胞过程都有关系。要了解这种蛋白质是如何调控一系列过程的,还需要进一步阐明。为此,我们研究了脂质代谢,并使用 RNAseq 策略比较了野生型和 Tspo 基因敲除(KO)小鼠肝脏中的转录本丰度。在 KO 小鼠肝脏中,胆固醇、甘油三酯和磷脂的水平显著升高。胆固醇平衡基因的表达明显下调。差异表达的测定结果表明,许多基因在 KO 动物体内要么上调,要么下调。然而,结果中一个引人注目的现象是,KO 动物体内蛋白质降解蛋白的转录本减少了,而蛋白酶抑制剂却富集了。当使用 CEMiTool 分析整个丰度数据集时,发现了一个在 KO 动物中代表性不足的蛋白质模块。这些蛋白质随后可以组成一个由三个相互关联的簇组成的网络,簇的中心是细胞质核糖体蛋白质,其基因本体术语表明它们的翻译功能受到了损害。最大的集群以脂质代谢蛋白为主,但也包含不同的铁代谢和行为系统。第三组主要是电子传递链和氧化磷酸化的蛋白质。这些发现表明,TSPO 有助于脂质代谢、活性氧解毒和氧化磷酸化,并能调节线粒体逆行信号。
Dysregulation of lipid metabolism in the liver of Tspo knockout mice
The translocator protein, TSPO, has been implicated in a wide range of cellular processes exerted from its position in the outer mitochondrial membrane from where it influences lipid metabolism and mitochondrial oxidative activity. Understanding how this protein regulates a profusion of processes requires further elucidation and to that end we have examined lipid metabolism and used an RNAseq strategy to compare transcript abundance in wildtype and Tspo knockout (KO) mouse liver. The levels of cholesterol, triglyceride and phospholipid were significantly elevated in the KO mouse liver. The expression of cholesterol homeostasis genes was markedly downregulated. Determination of the differential expression revealed that many genes were either up- or downregulated in the KO animals. However, a striking observation within the results was a decrease of transcripts for protein degradation proteins in KO animals while protease inhibitors were enriched. When the entire abundance data-set was analysed with CEMiTool, and revealed a module of proteins that were under-represented in the KO animals. These could subsequently be formed into a network comprising three interlinked clusters at the centre of which were proteins of cytoplasmic ribosomes with gene ontology terms suggesting impairment to translation. The largest cluster was dominated by proteins of lipid metabolism but also contained disparate systems of iron metabolism and behaviour. The third cluster was dominated by proteins of the electron transport chain and oxidative phosphorylation. These findings suggest that TSPO contributes to lipid metabolism, detoxification of active oxygen species and oxidative phosphorylation, and regulates mitochondrial retrograde signalling.
期刊介绍:
BBA Molecular and Cell Biology of Lipids publishes papers on original research dealing with novel aspects of molecular genetics related to the lipidome, the biosynthesis of lipids, the role of lipids in cells and whole organisms, the regulation of lipid metabolism and function, and lipidomics in all organisms. Manuscripts should significantly advance the understanding of the molecular mechanisms underlying biological processes in which lipids are involved. Papers detailing novel methodology must report significant biochemical, molecular, or functional insight in the area of lipids.