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

Constance Ahowesso, Paul N Black, Nipun Saini, David Montefusco, Jessica Chekal, Chrysa Malosh, Craig W. Lindsley, Shaun R. Stauffer, Concetta C DiRusso

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)167-181
Number of pages15
JournalBiochemical Pharmacology
Volume98
Issue number1
DOIs
StatePublished - Nov 1 2015

Fingerprint

Cell death
Cell Death
Fatty Acids
Nonesterified Fatty Acids
Adipocytes
Cells
High-Throughput Screening Assays
Cell Line
Oxidative stress
Palmitates
Oleic Acid
Medical problems
Metabolites
Liver
Muscle Cells
Type 2 Diabetes Mellitus
Adipose Tissue
Pancreas
Hepatocytes
Screening

Keywords

  • Chemical compounds studied in this article 5′-bromo-5-phenyl-spiro[3H-1,3,4-thiadiazole-2,3′-indoline]-2′-one

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Chemical inhibition of fatty acid absorption and cellular uptake limits lipotoxic cell death. / Ahowesso, Constance; Black, Paul N; Saini, Nipun; Montefusco, David; Chekal, Jessica; Malosh, Chrysa; Lindsley, Craig W.; Stauffer, Shaun R.; DiRusso, Concetta C.

In: Biochemical Pharmacology, Vol. 98, No. 1, 01.11.2015, p. 167-181.

Research output: Contribution to journalArticle

Ahowesso, C, Black, PN, Saini, N, Montefusco, D, Chekal, J, Malosh, C, Lindsley, CW, Stauffer, SR & DiRusso, CC 2015, 'Chemical inhibition of fatty acid absorption and cellular uptake limits lipotoxic cell death', Biochemical Pharmacology, vol. 98, no. 1, pp. 167-181. https://doi.org/10.1016/j.bcp.2015.09.004
Ahowesso, Constance ; Black, Paul N ; Saini, Nipun ; Montefusco, David ; Chekal, Jessica ; Malosh, Chrysa ; Lindsley, Craig W. ; Stauffer, Shaun R. ; DiRusso, Concetta C. / Chemical inhibition of fatty acid absorption and cellular uptake limits lipotoxic cell death. In: Biochemical Pharmacology. 2015 ; Vol. 98, No. 1. pp. 167-181.
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