Acute exposure to fatty acids alters hepatic genes controlling branched‐chain amino acid degradation, inflammatory and acute phase response signaling, and liver x receptor/retinoid x receptor function

Abstract

Many transcriptional profiling studies have been performed to understand chronic hepatic steatosis. However, less is known about the gene expression changes in hepatocytes upon acute increases in fatty acid (FA) flux, as would occur during exercise‐induced lipolysis, prolonged fasting, etc. To address this question, we used a rat hepatoma cell line, McArdle RH7777, commonly used to model triglyceride (TG) mobilization and VLDL secretion. Cells were cultured for 24 h in the presence of 0.8 mM oleic acid complexed to BSA. Under these conditions cellular TG levels increased ten‐fold, as compared to BSA controls. Microarray analysis revealed that the top canonical pathways altered by oleic acid were 1) FA metabolism, 2) branched‐chain amino acid degradation, 3) acute phase response signaling, 4) lipopolysaccharide/interleukin‐1 mediated inhibition of retinoid x receptor function, and 5) liver x receptor/retinoid x receptor activation. These results indicate that acute exposure of hepatocytes to FA impacts several gene expression programs, including those involved in inflammation and the acute phase response. Candidate genes will be further investigated by RT‐PCR to elucidate the temporal and concentration dependence of gene expression changes associated with hepatic exposure to physiologic and pathophysiologic concentrations of FA. Support: RJR‐Leon Golberg Post‐Doctoral Fellowship to A.L.B.