An integrative systems genetic analysis of mammalian lipid metabolism

Abstract

Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity. There is an increasingly urgent need to understand the causal factors that contribute to excess lipid accumulation in the liver known as hepatosteatosis, and an equally important need to discover biomarkers and interventions for its early diagnosis and treatment. A major proportion of current and predicted global health burden stems from conditions in which hepatosteatosis is an underlying pathology 1. Defining the mechanisms that causally influence hepatosteatosis has historically proven challenging, largely owing to an ill-defined interaction between genetic and environmental factors 2. This, together with the insufficient ability for standard genome-wide association studies to capture the effect of environment on complex traits, probably explains why only a small fraction of the estimated 30% heritability for hepatosteatosis has been assigned to specific gene variants 3. Genetic reference panels (GRPs) have become a more tractable way of studying the influence of genetics and environment on complex traits, because unlike studies in humans, GRPs allow for accurate control of environment as well as access to critical metabolic tissues. Importantly, integrating intermediate phenotypes such as transcriptomics, Parker et al.

Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases

“…RNA was isolated from tissue as previously described 87 . Mouse tissues were homogenised in RNAzol, and RNA isolated using chloroform followed by isopropanol precipitation.…”

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

“…The relative position of GLO-1 as a downstream consequence of altered metabolism or as a driver of it, is highlighted by a recent systems genetic analysis which identified Glo1 as an important gene in the regulation of lipid metabolism. 50 While it is possible that the fat oxidation defect observed in Alkbh7 -/mice is downstream of GLO-1, our evidence favors a hormetic response of GLO-1 to glycative stress downstream of a fat-to-glucose switch as the more likely scenario.…”

Genetics’ Piece of the PI: Inferring the Origin of Complex Traits and Diseases from Proteome‐Wide Protein–Protein Interaction Dynamics

“…Advances in proteomics have since opened up the possibility to investigate the association of genomic variants with protein abundances . Studies using aptamer‐, immunoassay‐, or mass‐spectrometry‐based proteomics have shown how changes in protein abundance can be associated with variants both in cis and in trans. Notably, such proteome‐wide screens of pQTL have been conducted in yeast, mice, maize, human cell lines, and primary cell lines .…”