Chronic elevation of plasma
free fatty acid (FFA) levels is commonly associated with
obesity,
type 2 diabetes,
cardiovascular disease and some
cancers. Experimental evidence indicates FFA and their metabolites contribute to disease development through lipotoxicity. Previously, we identified a specific
fatty acid transport inhibitor CB16.2, a.k.a.
Lipofermata, using high throughput screening methods. In this study, efficacy of transport inhibition was measured in four cell lines that are models for myocytes (mmC2C12), pancreatic β-cells (rnINS-1E), intestinal epithelial cells (hsCaco-2), and hepatocytes (hsHepG2), as well as primary human adipocytes. The compound was effective in inhibiting uptake with IC50s between 3 and 6μM for all cell lines except human adipocytes (39μM). Inhibition was specific for long and very long chain
fatty acids but had no effect on medium chain
fatty acids (C6-C10), which are transported by passive diffusion. Derivatives of
Lipofermata were evaluated to understand structural contributions to activity.
Lipofermata prevented
palmitate-mediated oxidative stress, induction of BiP and CHOP, and cell death in a dose-dependent manner in hsHepG2 and rnINS-1E cells, suggesting it will prevent induction of
fatty acid-mediated cell death pathways and lipotoxic disease by channeling excess
fatty acids to adipose tissue and away from liver and pancreas. Importantly, mice dosed orally with
Lipofermata were not able to absorb (13)C-oleate demonstrating utility as an inhibitor of
fatty acid absorption from the gut.