Ketone bodies [beta-hydroxybutyrate (bHB) and acetoacetate] are mainly produced in the liver during prolonged fasting or starvation. bHB is a very efficient energy substrate for sustaining ATP production in peripheral tissues; importantly, its consumption is preferred over glucose. However, the majority of malignant cells, particularly cancer cells of neuroectodermal origin such as glioblastoma, are not able to use ketone bodies as a source of energy. Here, we report a novel observation that fenofibrate, a synthetic peroxisome proliferator-activated receptor alpha (PPARa) agonist, induces bHB production in melanoma and glioblastoma cells, as well as in neurospheres composed of non-transformed cells. Unexpectedly, this effect is not dependent on PPARa activity or its expression level. The fenofibrate-induced ketogenesis is accompanied by growth arrest and downregulation of transketolase, but the NADP/NADPH and GSH/GSSG ratios remain unaffected. Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic) therapeutic approaches against glioblastoma.

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Addition of antioxidants (in particular BHT) to the diet increases bioavailability of lipids and carbohydrates, which consequently may increase the risk of obesity development. The dose of antioxidants is a factor of fundamental importance, particularly for catechins: low doses increase absorption of lipids, whereas high doses exert the opposite effect.

Synthetic antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and tert-butylhydroquinone (TBHQ), have been widely used for many years to stabilise lipids in foods. Nonetheless, their effect on the bioavailability and metabolism of lipids stabilised with them still remains unknown. To investigate this issue, in vitro digestion of a model high-fat product (20 g fat/100 g) without antioxidants and supplemented with BHT, BHA and TBHQ (100 mg/kg) was conducted, followed by studies using the Caco-2 and Hep G2 cell lines. BHT, BHA and TBHQ increased intestinal absorption of triacylglycerols and modified the structure of chylomicrons (CM). The addition of BHT and TBHQ inhibited apolipoprotein-IV (apoA-IV) synthesis. At the same time, smaller chylomicrons were secreted, but their amount was greater than in the model product without antioxidants. In contrast, BHA activated apoA-IV synthesis, resulting in the formation of fewer but very large CMs. Of concern was the significant decrease in apoA-IV in cells upon the use of BHT and TBHQ, which can lead to obesity due to the lack of the sensation of feeling full after eating high-fat foods stabilised with these antioxidants. Furthermore, the efficiency of CM remnant (CMR) uptake by hepatocytes was inversely correlated with their size. The large CMRs generated for samples with BHA were not absorbed by hepatocytes, which can lead to atherosclerosis. The results of our in vitro study shed new light on the role of synthetic phenolic antioxidants used in food technology as potential obesity and atherosclerosis triggers and suggested the need for further research that will clearly separate antioxidants that promote the development of these diseases from those, which do not do that.