Systematic interrogation of functional genes underlying cholesterol and lipid homeostasis

IF 10.1 1区生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Genome Biology Pub Date : 2025-03-17 DOI:10.1186/s13059-025-03531-8

Haihuan Shan, Shuangshuang Fan, Quanrun Li, Ruipu Liang, Zhisong Chen, Shengnan Wang, Xiaofeng Wang, Yurong Li, Shuai Chen, Kun Yu, Teng Fei

{"title":"Systematic interrogation of functional genes underlying cholesterol and lipid homeostasis","authors":"Haihuan Shan, Shuangshuang Fan, Quanrun Li, Ruipu Liang, Zhisong Chen, Shengnan Wang, Xiaofeng Wang, Yurong Li, Shuai Chen, Kun Yu, Teng Fei","doi":"10.1186/s13059-025-03531-8","DOIUrl":null,"url":null,"abstract":"Dyslipidemia or hypercholesterolemia are among the main risk factors for cardiovascular diseases. Unraveling the molecular basis of lipid or cholesterol homeostasis would help to identify novel drug targets and develop effective therapeutics. Here, we adopt a systematic approach to catalog the genes underlying lipid and cholesterol homeostasis by combinatorial use of high-throughput CRISPR screening, RNA sequencing, human genetic variant association analysis, and proteomic and metabolomic profiling. Such integrative multi-omics efforts identify gamma-glutamyltransferase GGT7 as an intriguing potential cholesterol and lipid regulator. As a SREBP2-dependent target, GGT7 positively regulates cellular cholesterol levels and affects the expression of several cholesterol metabolism genes. Furthermore, GGT7 interacts with actin-dependent motor protein MYH10 to control low-density lipoprotein cholesterol (LDL-C) uptake into the cells. Genetic ablation of Ggt7 in mice leads to reduced serum cholesterol levels, supporting an in vivo role of Ggt7 during cholesterol homeostasis. Our study not only provides a repertoire of lipid or cholesterol regulatory genes from multiple angles but also reveals a causal link between a gamma-glutamyltransferase and cholesterol metabolism.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"19 1","pages":""},"PeriodicalIF":10.1000,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13059-025-03531-8","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Dyslipidemia or hypercholesterolemia are among the main risk factors for cardiovascular diseases. Unraveling the molecular basis of lipid or cholesterol homeostasis would help to identify novel drug targets and develop effective therapeutics. Here, we adopt a systematic approach to catalog the genes underlying lipid and cholesterol homeostasis by combinatorial use of high-throughput CRISPR screening, RNA sequencing, human genetic variant association analysis, and proteomic and metabolomic profiling. Such integrative multi-omics efforts identify gamma-glutamyltransferase GGT7 as an intriguing potential cholesterol and lipid regulator. As a SREBP2-dependent target, GGT7 positively regulates cellular cholesterol levels and affects the expression of several cholesterol metabolism genes. Furthermore, GGT7 interacts with actin-dependent motor protein MYH10 to control low-density lipoprotein cholesterol (LDL-C) uptake into the cells. Genetic ablation of Ggt7 in mice leads to reduced serum cholesterol levels, supporting an in vivo role of Ggt7 during cholesterol homeostasis. Our study not only provides a repertoire of lipid or cholesterol regulatory genes from multiple angles but also reveals a causal link between a gamma-glutamyltransferase and cholesterol metabolism.

查看原文本刊更多论文

系统检测胆固醇和脂质平衡的功能基因

血脂异常或高胆固醇血症是心血管疾病的主要危险因素之一。揭示脂质或胆固醇稳态的分子基础将有助于确定新的药物靶点和开发有效的治疗方法。在这里，我们采用了一种系统的方法，通过组合使用高通量CRISPR筛选、RNA测序、人类遗传变异关联分析以及蛋白质组学和代谢组学分析，对脂质和胆固醇稳态的基因进行了分类。这种整合的多组学研究发现-谷氨酰转移酶GGT7是一种有趣的潜在胆固醇和脂质调节剂。作为srebp2依赖性靶点， GGT7 正向调节细胞胆固醇水平并影响几种胆固醇代谢基因的表达。此外，GGT7与肌动蛋白依赖的运动蛋白MYH10相互作用，控制低密度脂蛋白胆固醇（LDL-C）进入细胞。在小鼠中基因消融 Ggt7 导致血清胆固醇水平降低，支持 Ggt7 在胆固醇稳态中的 体内 作用。我们的研究不仅从多个角度提供了脂质或胆固醇调节基因，而且揭示了γ -谷氨酰转移酶与胆固醇代谢之间的因果关系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Genome Biology Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

21.00

自引率

3.30%

发文量

241

审稿时长

2 months

期刊介绍： Genome Biology stands as a premier platform for exceptional research across all domains of biology and biomedicine, explored through a genomic and post-genomic lens. With an impressive impact factor of 12.3 (2022),* the journal secures its position as the 3rd-ranked research journal in the Genetics and Heredity category and the 2nd-ranked research journal in the Biotechnology and Applied Microbiology category by Thomson Reuters. Notably, Genome Biology holds the distinction of being the highest-ranked open-access journal in this category. Our dedicated team of highly trained in-house Editors collaborates closely with our esteemed Editorial Board of international experts, ensuring the journal remains on the forefront of scientific advances and community standards. Regular engagement with researchers at conferences and institute visits underscores our commitment to staying abreast of the latest developments in the field.