Isomeric lipid signatures reveal compartmentalised fatty acid metabolism in cancer

Cellular energy and biomass demands of cancer drive a complex dynamic between uptake of extracellular fatty acids (FA) and de novo synthesis. Given that oxidation of de novo synthesised FAs for energy would result in net-energy loss, there is an implication that FAs from these two sources must have distinct metabolic fates - however hitherto FAs were considered part of a common pool. To probe FA metabolic partitioning, cancer cells were supplemented with stable-isotope labelled FAs. Structural analysis of the resulting glycerophospholipids revealed that labelled FAs from uptake were largely incorporated to canonical (sn-)positions on the glycerol backbone. Surprisingly, labelled FA uptake disrupted canonical isomer patterns of the unlabelled lipidome and induced repartitioning of n-3 and n-6 polyunsaturated-FAs into glycerophospholipid classes. These structural changes evidence differences in the metabolic fate of FAs derived from uptake or de novo sources and demonstrate unique signalling and remodelling behaviours usually hidden to conventional lipidomics.

Metabolic Fate of Dietary Glucosinolates and Their Metabolites: A Role for the Microbiome

Robust evidence shows that phytochemicals from cruciferous vegetables, like broccoli, are associated with numerous health benefits. The anti-cancer properties of these foods are attributed to bioactive isothiocyanates (ITCs) and indoles, phytochemicals generated from biological precursor compounds called glucosinolates. ITCs, and particularly sulforaphane (SFN), are of intense interest as they block the initiation, and suppress the progression of cancer, through genetic and epigenetic mechanisms. The efficacy of these compounds is well-demonstrated in cell culture and animal models, however, high levels of inter-individual variation in absorption and excretion of ITCs is a significant barrier to the use of dietary glucosinolates to prevent and treat disease. The source of inter-individual ITC variation has yet to be fully elucidated and the gut microbiome may play a key role. This review highlights evidence that the gut microbiome influences the metabolic fate and activity of ITCs. Human feeding trials have shown inter-individual variations in gut microbiome composition coincides with variations in ITC absorption and excretion, and some bacteria produce ITCs from glucosinolates. Additionally, consumption of cruciferous vegetables can alter the composition of the gut microbiome and shift the physiochemical environment of the gut lumen, influencing the production of phytochemicals. Microbiome and diet induced changes to ITC metabolism may lead to the decrease of cancer fighting phytochemicals such as SFN and increase the production of biologically inert ones like SFN-nitrile. We conclude by offering perspective on the use of novel “omics” technologies to elucidate the interplay of the gut microbiome and ITC formation.

Intestinal and Hepatic Uptake of Dietary Peroxidized Lipids and Their Decomposition Products, and Their Subsequent Effects on Apolipoprotein A1 and Paraoxonase1

Both pro- and antiatherosclerotic effects have been ascribed to dietary peroxidized lipids. Confusion on the role of peroxidized lipids in atherosclerotic cardiovascular disease is punctuated by a lack of understanding regarding the metabolic fate and potential physiological effects of dietary peroxidized lipids and their decomposition products. This study sought to determine the metabolic fate and physiological ramifications of 13-hydroperoxyoctadecadienoic acid (13-HPODE) and 13-HODE (13-hydroxyoctadecadienoic acid) supplementation in intestinal and hepatic cell lines, as well as any effects resulting from 13-HPODE or 13-HODE degradation products. In the presence of Caco-2 cells, 13-HPODE was rapidly reduced to 13-HODE. Upon entering the cell, 13-HODE appears to undergo decomposition, followed by esterification. Moreover, 13-HPODE undergoes autodecomposition to produce aldehydes such as 9-oxononanoic acid (9-ONA). Results indicate that 9-ONA was oxidized to azelaic acid (AzA) rapidly in cell culture media, but AzA was poorly absorbed by intestinal cells and remained detectable in cell culture media for up to 18 h. An increased apolipoprotein A1 (ApoA1) secretion was observed in Caco-2 cells in the presence of 13-HPODE, 9-ONA, and AzA, whereas such induction was not observed in HepG2 cells. However, 13-HPODE treatments suppressed paraoxonase 1 (PON1) activity, suggesting the induction of ApoA1 secretion by 13-HPODE may not represent functional high-density lipoprotein (HDL) capable of reducing oxidative stress. Alternatively, AzA induced both ApoA1 secretion and PON1 activity while suppressing ApoB secretion in differentiated Caco-2 cells but not in HepG2. These results suggest oxidation of 9-ONA to AzA might be an important phenomenon, resulting in the accumulation of potentially beneficial dietary peroxidized lipid-derived aldehydes.