Physiological and metabolomic consequences of reduced expression of the Drosophila brummer triglyceride Lipase

Disruption of lipolysis has widespread effects on intermediary metabolism and organismal phenotypes. Defects in lipolysis can be modeled in Drosophila melanogaster through genetic manipulations of brummer (bmm), which encodes a triglyceride lipase orthologous to mammalian Adipose Triglyceride Lipase. RNAi-mediated knock-down of bmm in all tissues or metabolic specific tissues results in reduced locomotor activity, altered sleep patterns and reduced lifespan. Metabolomic analysis on flies in which bmm is downregulated reveals a marked reduction in medium chain fatty acids, long chain saturated fatty acids and long chain monounsaturated and polyunsaturated fatty acids, and an increase in diacylglycerol levels. Elevated carbohydrate metabolites and tricarboxylic acid intermediates indicate that impairment of fatty acid mobilization as an energy source may result in upregulation of compensatory carbohydrate catabolism. bmm downregulation also results in elevated levels of serotonin and dopamine neurotransmitters, possibly accounting for the impairment of locomotor activity and sleep patterns. Physiological phenotypes and metabolomic changes upon reduction of bmm expression show extensive sexual dimorphism. Altered metabolic states in the Drosophila model are relevant for understanding human metabolic disorders, since pathways of intermediary metabolism are conserved across phyla.

Physiological and Metabolomic Consequences of Reduced Expression of the Drosophila brummer Triglyceride Lipase

Disruption of lipolysis has widespread effects on intermediary metabolism and organismal phenotypes. Defects in lipolysis can be modeled in Drosophila melanogaster through genetic manipulations of brummer ( bmm ), which encodes a triglyceride lipase orthologous to mammalian Adipose Triglyceride Lipase. RNAi-mediated knock-down of bmm in all tissues or metabolic specific tissues results in reduced locomotor activity, altered sleep patterns and reduced lifespan. Metabolomic analysis on flies in which bmm is downregulated reveals a marked reduction in medium chain fatty acids, long chain saturated fatty acids and long chain monounsaturated and polyunsaturated fatty acids, and an increase in diacylglycerol levels. Elevated carbohydrate metabolites and tricarboxylic acid intermediates indicate that impairment of fatty acid mobilization as an energy source may result in upregulation of compensatory carbohydrate catabolism. bmm downregulation also results in elevated levels of serotonin and dopamine neurotransmitters, possibly accounting for the impairment of locomotor activity and sleep patterns. Physiological phenotypes and metabolomic changes upon reduction of bmm expression show extensive sexual dimorphism. Altered metabolic states in the Drosophila model are relevant for understanding human metabolic disorders, since pathways of intermediary metabolism are conserved across phyla.

The expanding world of metabolic enzymes moonlighting as RNA binding proteins

RNA binding proteins play key roles in many aspects of RNA metabolism and function, including splicing, transport, translation, localization, stability and degradation. Within the past few years, proteomics studies have identified dozens of enzymes in intermediary metabolism that bind to RNA. The wide occurrence and conservation of RNA binding ability across distant branches of the evolutionary tree suggest that these moonlighting enzymes are involved in connections between intermediary metabolism and gene expression that comprise far more extensive regulatory networks than previously thought. There are many outstanding questions about the molecular structures and mechanisms involved, the effects of these interactions on enzyme and RNA functions, and the factors that regulate the interactions. The effects on RNA function are likely to be wider than regulation of translation, and some enzyme–RNA interactions have been found to regulate the enzyme's catalytic activity. Several enzyme–RNA interactions have been shown to be affected by cellular factors that change under different intracellular and environmental conditions, including concentrations of substrates and cofactors. Understanding the molecular mechanisms involved in the interactions between the enzymes and RNA, the factors involved in regulation, and the effects of the enzyme–RNA interactions on both the enzyme and RNA functions will lead to a better understanding of the role of the many newly identified enzyme–RNA interactions in connecting intermediary metabolism and gene expression.

Comprehensive molecular pharmacodynamic assessment identifies response markers of intermediary metabolism associated with BPM 31510-IV treatment in advanced glioblastoma multiforme patients.

2059 Background: BPM 31510-IV is a drug-lipid conjugate nanodispersion containing oxidized Coenzyme Q10 (CoQ10) in clinical development for glioblastoma multiforme (GBM). In a recently concluded Phase 1 study of BPM 31510-IV (NCT03020602), in addition to safety and tolerability, longitudinal pharmacodynamic samples (20 samples/cycle of 28 days) were collected at various times in patient’s refractory to radiation, temozolomide, and bevacizumab. Methods: Comprehensive multi-omic (proteomic, lipidomic, metabolomic) profiles were generated from buffy coat (proteomics only), plasma, and urine matrices. These data were further analyzed using bAIcis, a Bayesian statistics based artificial intelligence (AI) software, creating causal networks linking clinical information and endpoints to molecular composition of diverse biomatrices of patients prior to, as well as during, treatment with BPM 31510-IV. Twelve subjects comprised the intent to treat population (ITT) which were stratified across days of treatment (DR1; ≤28 days; DLT period; n=6) and (DR2, OS; >28 days; n=6). Bayesian networks and regression analysis were performed on the outputs of the analysis. Molecular analyte panels (combination of proteins, lipids, and metabolites) descriptive of progression free survival (PFS), adverse events (possibly/probably related to BPM 31510-IV), and of overall survival (OS) were generated. Results: Significant alteration (p<0.05) of metabolically associated protein and critical metabolite drivers of intermediary metabolism were identified as causally related to PFS. Significant quantitative changes in levels of several proteins (buffy coat) and metabolites (urine) were identified with probable or possible associations to adverse events in BPM 31510-IV treated subjects. Conclusions: Overall, alterations in proteins and metabolites influencing mitochondrial function and intermediary metabolism that differentiated responders versus non-responders and identified potential markers of adverse events associated with BPM 31510-IV exposure were identified and will be further explored for complementary diagnostic utility.