TY - JOUR
T1 - Chemical inhibition of fatty acid absorption and cellular uptake limits lipotoxic cell death
AU - Ahowesso, Constance
AU - Black, Paul N.
AU - Saini, Nipun
AU - Montefusco, David
AU - Chekal, Jessica
AU - Malosh, Chrysa
AU - Lindsley, Craig W.
AU - Stauffer, Shaun R.
AU - DiRusso, Concetta C.
N1 - Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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 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.
AB - 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 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.
KW - Chemical compounds studied in this article 5′-bromo-5-phenyl-spiro[3H-1,3,4-thiadiazole-2,3′-indoline]-2′-one
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U2 - 10.1016/j.bcp.2015.09.004
DO - 10.1016/j.bcp.2015.09.004
M3 - Article
C2 - 26394026
AN - SCOPUS:84943376122
SN - 0006-2952
VL - 98
SP - 167
EP - 181
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 1
ER -