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Background <p>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.</p> Results <p>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, <i>GGT7</i> 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 <i>Ggt7</i> in mice leads to reduced serum cholesterol levels, supporting an in vivo role of <i>Ggt7</i> during cholesterol homeostasis.</p> Conclusions <p>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.</p>

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Systematic interrogation of functional genes underlying cholesterol and lipid homeostasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月17日

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

摘要

Background

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.

Results

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.

Conclusions

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.