Shared and distinct lipid-lipid interactions in plasma and affected tissues in a diabetic mouse model

Abstract

Lipids are ubiquitous metabolites with diverse functions; abnormalities in lipid metabolism appear to be related to complications from multiple diseases, including type 2 diabetes. Through technological advances, the entire lipidome has been characterized and researchers now need computational approaches to better understand lipid network perturbations in different diseases. Using a mouse model of type 2 diabetes with microvascular complications, we examined lipid levels in plasma and in renal, neural, and retinal tissues to identify shared and distinct lipid abnormalities. We used correlation analysis to construct interaction networks in each tissue, to associate changes in lipids with changes in enzymes of lipid metabolism, and to identify overlap of coregulated lipid subclasses between plasma and each tissue to define subclasses of plasma lipids to use as surrogates of tissue lipid metabolism. Lipid metabolism alterations were mostly tissue specific in the kidney, nerve, and retina; no lipid changes correlated between the plasma and all three tissue types. However, alterations in diacylglycerol and in lipids containing arachidonic acid, an inflammatory mediator, were shared among the tissue types, and the highly saturated cholesterol esters were similarly coregulated between plasma and each tissue type in the diabetic mouse. Our results identified several patterns of altered lipid metabolism that may help to identify pathogenic alterations in different tissues and could be used as biomarkers in future research into diabetic microvascular tissue damage.

New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism

“…In line with these findings, extensive lipid accumulation has been reported within kidney glomeruli and tubulointerstitium in individuals with type 2 diabetes who had diabetic kidney disease [63]. Moreover, using postmortem human retina samples, we recently obtained data suggesting alterations in lipid metabolism in retinas from donors with diabetic retinopathy (P. E. Fort, unpublished data), consistent with the reduction observed in BKS db/db mice [30]. The importance of these findings is highlighted by the observation that genetic deletion of the fatty acid synthase gene in the neuroretina leads to progressive neurodegeneration, with synaptic dysfunction, neuronal cell apoptosis and visual impairment [64].…”

“…To our knowledge, no other study has examined alterations in glucose metabolism across complications within the same animal model of diabetes. Besides this study, transcriptomic studies, in combination with metabolomic and proteomic analysis of tissues from both animal models of diabetes and human biopsies from diabetic individuals, have implicated both glucosedependent and independent mechanisms [26][27][28][29][30][31][32][33]. Using metabolomics analysis, Priyadarsini et al found no effect of glucose-derived metabolite flux in human corneal stroma of individuals with type 1 and type 2 diabetes [33].…”

“…On the other hand, Freeman et al showed an increase in glucose and polyol pathway intermediates in sciatic nerves of a streptozotocin (STZ)-induced rat model of type 1 diabetes using an integrated proteomics and metabolomics approach [32]. Importantly, all these studies support the involvement of key factors other than glucose in the pathogenesis of diabetic kidney disease, retinopathy and neuropathy, including a central role for disturbances in lipid metabolism [26][27][28][29][30][31][32][33][34].…”

“…To address this knowledge gap, our group has used integrated approaches to link systemic and tissue-specific lipid metabolism to diabetic complications pathologies [26,31]. We have measured levels of multiple lipid species in plasma, kidney, retina and nerve in the BKS db/db mouse [30]. In doing so, we uncovered tissue-specific alterations in several lipid classes, both in their level and directionality, which were defined by class, carbon side-chain length and saturation levels (Fig.…”

“…Cardiolipins (inner mitochondrial membrane lipids) are important for mitochondrial structure and mitochondrial metabolism. We recently identified an increase in immature cardiolipins in the diabetic kidney [30], which is associated with reduced bioenergetics [92], a hallmark of diabetic kidney disease [93]. Interestingly, preserving mitochondrial structure with a cardiolipin-binding peptide maintains mitochondrial function in the kidney [94,95], reverses visual decline in diabetic mice [96] and improves bioenergetics and mitochondrial trafficking in neurons [97].…”