Meredith Brown and Sarah Compton contributed equally to this study
Metabolomic signatures in lipid-loaded HepaRGs reveal pathways involved in steatotic progression
Article first published online: 13 JUN 2013
Copyright © 2013 The Obesity Society
Volume 21, Issue 12, pages E561–E570, December 2013
How to Cite
Brown, M. V., Compton, S. A., Milburn, M. V., Lawton, K. A. and Cheatham, B. (2013), Metabolomic signatures in lipid-loaded HepaRGs reveal pathways involved in steatotic progression. Obesity, 21: E561–E570. doi: 10.1002/oby.20440
Disclosure: MB is employed by Metabolon and has equity interests in Metabolon. SC is employed by ZenBio. MM is employed by Metabolon and has equity interests in Metabolon. KL is employed by Metabolon and has equity interests in Metabolon. BC is employed by ZenBio.
Funding agencies: This study was supported by a grant from the National Institute of Health DK088430. Support for MB and SC was received from the North Carolina Biotechnology Center Industrial Fellowship Program.
- Issue published online: 3 DEC 2013
- Article first published online: 13 JUN 2013
- Accepted manuscript online: 20 MAR 2013 02:25AM EST
- Manuscript Accepted: 21 FEB 2013
- Manuscript Received: 14 NOV 2012
A spectrum of disorders including simple steatosis, nonalcoholic steatohepatitis, fibrosis, and cirrhosis is described by nonalcoholic fatty liver disease (NAFLD). With the increased prevalence of obesity, and consequently NAFLD, there is a need for novel therapeutics in this area. To facilitate this effort, a cellular model of hepatic steatosis was developed using HepaRG cells and the resulting biochemical alterations were determined.
Design and Methods
Using global metabolomic profiling, by means of a novel metabolite extraction procedure, the metabolic profiles in response to the saturated fatty acid palmitate, and a mixture of saturated and unsaturated fatty acids, palmitate and oleate (1:2) were examined.
We observed elevated levels of the branched chain amino acids, tricarboxylic acid cycle intermediates, sphingosine and acylcarnitines, and reduced levels of carnitine in the steatotic HepaRG model with both palmitate and palmitate:oleate treatments. In addition, elevated levels of diacylglycerols and monoacylglycerols as well as altered bile acid metabolism were selectively displayed by palmitate-induced steatotic cells.
Biochemical changes in pathways important in the transition to hepatic steatosis including insulin resistance, altered mitochondrial metabolism, and oxidative stress are revealed by this global metabolomic approach. Moreover, the utility of this in vitro model for investigating the mechanisms of steatotic progression, insulin resistance, and lipotoxicity in NAFLD was demonstrated.