Systematic interrogation of functional genes underlying cholesterol and lipid homeostasis

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.