From GWAS to GEMMs: Sestrin1 and cholesterol biosynthesis

Sestrin1 regulates hepatic cholesterol synthesis and circulating lipid concentrations. Dyslipidemia is a strongly inherited risk factor for coronary artery disease. Although human genome-wide association studies (GWAS) have previously found a number of genome-wide significant loci that are associated with circulating lipid concentrations, few of the identified loci have translated to the discovery of unknown lipid-regulating genes or led to new therapeutics. In this study, Li and colleagues integrated human GWAS data with mouse liver genome-wide transcriptomic and proteomic data to identify genes that regulate circulating lipids. The authors initially identified cholesterol synthesis gene sets from mouse liver datasets and then cross-referenced these genes with the Global Lipid Genetics Consortium human GWAS data, leading to the identification of 25 cholesterol metabolism–related genes. To determine whether these genes had functional roles in regulating cholesterol homeostasis, in vivo animal studies were performed to determine how high fat diet feeding, 3-hydroxy-3-methyl-glutaryl Coenzyme A (HMG CoA) reductase inhibitor therapy, cholesterol depletion, and silencing of HMG CoA synthase altered the expression of these genes. Comparing the functionally validated genes against the Million Veteran Program (MVP) and UK Biobank GWAS datasets resulted in the identification of just one common gene: Sestrin 1 (Sesn1). Genetically modified mouse models (GEMMs) of homozygous and heterozygous Sesn1 whole-body and liver-specific Sesn1 knockouts displayed elevated plasma very low density lipoprotein (VLDL), cholesterol, and triglycerides. Li and colleagues further discovered that Sesn1 regulated cholesterol biosynthesis in liver, and that Sesn1 knockout led to reduced phosphorylation of AMP activated protein kinase (AMPK) and acetyl CoA carboxylase (ACC), a known regulator of lipid biosynthesis. This paper identified Sestrin 1 as a regulator of hepatic lipid synthesis and circulating lipid concentrations. However, future work will need to show if Sestrin 1 expression is reduced during Western diet feeding in humans, if differences in hepatic expression of Sestrin1 modify circulating lipids in people, or if increasing Sestrin 1 expression in the liver could be a therapeutic strategy for dyslipidemia.