Chemical inhibition of fatty acid absorption and cellular uptake limits lipotoxic cell death

Authors

Constance Ahowesso, University of Nebraska Lincoln
Paul N. Black, University of Nebraska-LincolnFollow
Nipun Saini, University of Nebraska-LincolnFollow
David Montefusco, University of Nebraska Lincoln
Jessica Chekal, University of Nebraska – Lincoln
Chrysa Malosh, Vanderbilt University Medical Center
Craig W. Lindsley, Vanderbilt University Medical Center
Shaun R. Stauffer, Vanderbilt University Medical Center
Concetta DiRusso, University of Nebraska - LincolnFollow

Date of this Version

11-2015

Citation

Published in final edited form as: Biochem Pharmacol. 2015 November 1; 98(1): 167–181. doi:10.1016/j.bcp.2015.09.004.

Biochem Pharmacol. Author manuscript; available in PMC 2016 November 01.

Comments

Copyright 2015 Elsevier. Used by permission.

Abstract

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 ß-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 6 μM for all cell lines except human adipocytes (39 μM). 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 ¹³C-oleate demonstrating utility as an inhibitor of fatty acid absorption from the gut.