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Journal of Biochemistry Advance Access originally published online on August 19, 2008
Journal of Biochemistry 2008 144(5):599-607; doi:10.1093/jb/mvn105
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© 2008 The Japanese Biochemical Society

Saturated Fatty Acids Inhibit Hepatic Insulin Action by Modulating Insulin Receptor Expression and Post-receptor Signalling

Mark W. Ruddock*, Andrew Stein, Edwin Landaker, Jun Park, Robert C. Cooksey, Donald McClain and Mary-Elizabeth Patti

Research Division, Cellular & Molecular Physiology, Joslin Diabetes Centre, and Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA

*To whom correspondence should be addressed. Tel: +44(0)-28-9442-2413, Fax: +44(0)-28-9445-2912, E-mail: mark.ruddock{at}randox.com

Received May 8, 2008; Accepted August 13, 2008


  Abstract

Free fatty acids (FFAs) are proposed to play a pathogenic role in both peripheral and hepatic insulin resistance. We have examined the effect of saturated FFA on insulin signalling (100 nM) in two hepatocyte cell lines. Fao hepatoma cells were treated with physiological concentrations of sodium palmitate (0.25 mM) (16:0) for 0.25–48 h. Palmitate decreased insulin receptor (IR) protein and mRNA expression in a dose- and time-dependent manner (35% decrease at 12 h). Palmitate also reduced insulin-stimulated IR and IRS-2 tyrosine phosphorylation, IRS-2-associated PI 3-kinase activity, and phosphorylation of Akt, p70 S6 kinase, GSK-3 and FOXO1A. Palmitate also inhibited insulin action in hepatocytes derived from wild-type IR (+/+) mice, but was ineffective in IR-deficient (–/–) cells. The effects of palmitate were reversed by triacsin C, an inhibitor of fatty acyl CoA synthases, indicating that palmitoyl CoA ester formation is critical. Neither the non-metabolized bromopalmitate alone nor the medium chain fatty acid octanoate (8:0) produced similar effects. However, the CPT-1 inhibitor (±)-etomoxir and bromopalmitate (in molar excess) reversed the effects of palmitate. Thus, the inhibition of insulin signalling by palmitate in hepatoma cells is dependent upon oxidation of fatty acyl-CoA species and requires intact insulin receptor expression.

Key Words: β-oxidation, insulin signalling, insulin resistance, liver, palmitate

Abbreviations: C16, palmitate; DAG, diacylglycerol; FFA, free fatty acid; IR, insulin receptor; IRS, insulin receptor substrate; PKC, protein kinase C


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