Omics-Driven Systems Interrogation of Metabolic Dysregulation in COVID-19 Pathogenesis.

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.

Integration of lipidomics and metabolomics for in-depth understanding of cellular mechanism and disease progression.

Mass spectrometry (MS)-based omics technologies are now widely used to profile small molecules in multiple matrices to confer comprehensive snapshots of cellular metabolic phenotypes. The metabolomes of cells, tissues, and organisms comprise a variety of molecules including lipids, amino acids, sugars, organic acids, and so on. Metabolomics mainly focus on the hydrophilic classes, while lipidomics has emerged as an independent omics owing to the complexities of the organismal lipidomes. The potential roles of lipids and small metabolites in disease pathogenesis have been widely investigated in various human diseases, but system-level understanding is largely lacking, which could be partly attributed to the insufficiency in terms of metabolite coverage and quantitation accuracy in current analytical technologies. While scientists are continuously striving to develop high-coverage omics approaches, integration of metabolomics and lipidomics is becoming an emerging approach to mechanistic investigation. Integration of metabolome and lipidome offers a complete atlas of the metabolic landscape, enabling comprehensive network analysis to identify critical metabolic drivers in disease pathology, facilitating the study of interconnection between lipids and other metabolites in disease progression. In this review, we summarize omics-based findings on the roles of lipids and metabolites in the pathogenesis of selected major diseases threatening public health. We also discuss the advantages of integrating lipidomics and metabolomics for in-depth understanding of molecular mechanism in disease pathogenesis.

Plasma lipidomic profiling in murine mutants of Hermansky-Pudlak syndrome reveals differential changes in pro- and anti-atherosclerotic lipids.

Atherosclerosis is characterized by the accumulation of lipid-rich plaques in the arterial wall. Its pathogenesis is very complicated and has not yet been fully elucidated. It is known that dyslipidemia is a major factor in atherosclerosis. Several different Hermansky-Pudlak syndrome (HPS) mutant mice have been shown either anti-atherosclerotic or atherogenic phenotypes, which may be mainly attributed to corresponding lipid perturbation. To explore the effects of different HPS proteins on lipid metabolism and plasma lipid composition, we analyzed the plasma lipid profiles of three HPS mutant mice, pa (Hps9-/-), ru (Hps6-/-), ep (Hps1-/-), and wild-type (WT) mice. In pa and ru mice, some pro-atherosclerotic lipids, e.g. ceramide (Cer) and diacylglycerol (DAG), were down-regulated whereas triacylglycerol (TAG) containing docosahexaenoic acid (DHA) (22:6) fatty acyl was up-regulated when compared with WT mice. Several pro-atherosclerotic lipids including phosphatidic acid (PA), lysophosphatidylserine (LPS), sphingomyelin (SM), and cholesterol (Cho) were up-regulated in ep mice compared with WT mice. The lipid droplets in hepatocytes showed corresponding changes in these mutants. Our data suggest that the pa mutant resembles the ru mutant in its anti-atherosclerotic effects, but the ep mutant has an atherogenic effect. Our findings may provide clues to explain why different HPS mutant mice exhibit distinct anti-atherosclerotic or atherogenic effects after being exposed to high-cholesterol diets.

An integrated method for direct interrogation of sphingolipid homeostasis in the heart and brain tissues of mice through postnatal development up to reproductive senescence.

Development of rapid metabolomic methods poised for pathway discovery is expected to facilitate the identification of therapeutic candidates in the metabolomic approach to translational medicine. Using sphingolipid homeostasis as a prototype, we present herein an integrated method to facilitate a fast interrogation of altered sphingolipid (and phospholipid) metabolism associated with perturbed endolysosomal functions in mammalian systems. Constructed upon high performance liquid chromatography coupled to mass spectrometry, this method allows semi-quantitative measurements of more than 300 individual species within 20 min. The method was applied to investigate cardiac- and neural-specific developmental changes in sphingolipid regulation from the postnatal stage to reproductive senescence in mice, revealing that endogenous lysobisphosphatidic acids and specific complex glycosphingolipids are tightly co-regulated to foster concerted reductions in sphingolipid levels at distinct stages of postnatal development. Our lipidomic data suggest that such changing regulatory patterns in sphingolipid homeostasis is attributed to differential endolysosomal degradation of complex sphingolipids, which may be critical in ensuring efficient sphingolipid catabolism and organismal health at each stage of postnatal development.