Integrative Analyses Reveal Tstd1 as a Potential Modulator of HDL Cholesterol and Mitochondrial Function in Mice.

Adi Zheng,Zhihui Feng,Hao Li,Jiankang Liu

doi:10.3390/cells10112976

Abstract

High-density lipoprotein (HDL) cholesterol levels are closely associated with human health and diseases. To identify genes modulating plasma HDL levels, we integrated HDL measurements and multi-omics data collected from diverse mouse cohorts and combined a list of systems genetics methods, including quantitative trait loci (QTL) mapping analysis, mediation analysis, transcriptome-wide association analysis (TWAS), and correlation analysis. We confirmed a significant and conserved QTL for plasma HDL on chromosome 1 and identified that Tstd1 liver transcript correlates with plasma HDL in several independent mouse cohorts, suggesting Tstd1 may be a potential modulator of plasma HDL levels. Correlation analysis using over 70 transcriptomics datasets in humans and mice revealed consistent correlations between Tstd1 and genes known to be involved in cholesterol and HDL regulation. Consistent with strong enrichment in gene sets related to cholesterol and lipoproteins in the liver, mouse strains with high Tstd1 exhibited higher plasma levels of HDL, total cholesterol and other lipid markers. GeneBridge using large-scale expression datasets identified conserved and positive associations between TSTD1/Tstd1 and mitochondrial pathways, as well as cholesterol and lipid pathways in human, mouse and rat. In summary, we identified Tstd1 as a new modulator of plasma HDL and mitochondrial function through integrative systems analyses, and proposed a new mechanism of HDL modulation and a potential therapeutic target for relevant diseases. This study highlights the value of such integrative approaches in revealing molecular mechanisms of complex traits or diseases.

Highlights

High-density lipoprotein (HDL), a type of cholesterol with beneficial effects, possesses diverse anti-inflammatory, anti-oxidative and anti-apoptotic properties
Our study revealed Tstd1 as a new modulator of plasma HDL levels and mitochondrial function, and proposed a potential target for preventing and treating diseases related to HDL dysregulation
Sex and diet showed a strong influence on plasma HDL levels—males had higher HDL than females regardless of the diets, and mice fed with high-fat/highsucrose diet (HFHS) had higher HDLs than those on a normal diet (Figure 1)

Summary

Introduction

High-density lipoprotein (HDL), a type of cholesterol with beneficial effects, possesses diverse anti-inflammatory, anti-oxidative and anti-apoptotic properties. The dysregulation of HDL is related to many diseases including metabolic diseases [1,2,3], cardiovascular diseases [4,5,6,7,8], cancer [9,10,11], and kidney diseases [12]. Raising HDL levels has been considered an effective strategy to lower the risk of related diseases [2,5,11]. The detailed mechanism underpinning HDL metabolism is still poorly understood. The intrinsic mechanism of the influence of mitochondria on HDL is unclear. Understanding the interplay between mitochondria and HDL will be useful for understanding the pathogenesis of relevant diseases

Methods

Results

Conclusion