Integrating Mouse and Human Genetic Data to Move beyond GWAS and Identify Causal Genes in Cholesterol Metabolism

Abstract

Highlights d Systematic method to combine mouse liver network and human lipid GWAS for discovery d Identification of a conserved liver cholesterol module across mouse populations d Prioritization of genes replicated in mouse and associated with human lipid traits d Validation of Sestrin1 as a gene that regulates cholesterol biosynthesis

A unified framework for joint-tissue transcriptome-wide association and Mendelian randomization analysis

“…In addition, MR-JTI identified six genes from the literature-based silver standard ( Methods ), which is greater than the other approaches ( Supplementary Table 9 ). Notably, we found that the 138 genes were significantly enriched for genes in the silver standard gene list ( P < 0.001, the overlap [6] is 13.3 times as much as the expected count [0.45]) and, separately, in a conserved “cholesterol biosynthetic process” module in mice ( P = 0.013, the overlap [16] is 1.68 times as much as the expected count [9.53]) 25 ( Supplementary Note ). This analysis provides additional support for 16 of the MR-JTI significant genes (including PLTP , FASD3 , and POLK , labeled in Supplementary Table 8 and 9 ).…”

COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads to cytokine storm

“…Cholesterol biosynthesis is inhibited by the expression of SESN-1 and PCSK9, and is regulated by transcription factor and NRLP3 inflammasome. 24 , 43 A recent study has confirmed that cholesterol biosynthesis is increased by the activity of SREBP-2; but at the same time, SESN-1 and PCSK9 are expressed and inhibitory results were demonstrated. 24 In severe COVID-19 patients, the biosynthesis of cholesterol such as intracellular HDL needs to be promoted and then subsequent homeostasis takes place as a result of the increase in SREBP-2 activity.…”

“…A recently published paper showed that Sestrin1 (SESN1) transcription is regulated by SREBP-2 in cells, demonstrating that SESN1 inhibits cholesterol biosynthesis. 24 The results showed a significant reduction in plasma cholesterol levels in cholesterol-fed SESN1 +/− and SESN1 −/− mice but not in control mice (Sesn1 +/+ ), indicating that the SESN1 affects plasma cholesterol in a liver-specific manner via regulation of cholesterol biosynthesis. It is reported that SESN1 activates AMP kinase (AMPK) and inhibits rapamycin complex 1 (mTORC1).…”

“… 25 – 27 The recently published data demonstrated that after cholesterol feeding, SESN1 −/− mouse livers had significantly reduced phosphorylated AMPK and unchanged mTORC1, indicating that SESN1 functions to repress cholesterol biosynthesis via activating AMP kinase pathway. 24 However, the exact mechanism of how cholesterol biosynthesis of SREBP-2 and SESN1 is associated with induction of inflammation during infections remain elusive.…”

Systematically Sifting Big Data to Identify Novel Causal Genes for Human Traits

“…In this issue of Cell Metabolism, Li et al (2020) report their creative use of an iterative sifting process using computational approaches to prioritize novel genes associated with plasma cholesterol levels. They subjected a focused candidate list to extensive functional validation in cell culture, and ultimately using in vivo mouse experiments, provided compelling evidence to add SESTRIN1 as a novel component of the cholesterol biosynthetic pathway (Figure 1).…”