Mechanism of Free Fatty Acid Effects on Hepatocyte Insulin Receptor Binding and Processing

M. M. Hennes, E. Shrago, A. H. Kissebah

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

We determined whether the paimitate effects on hepatocyte insulin receptor binding and post‐receptor trafficking were mediated by accelerated mitochondrial (β‐oxidation or accumulation of intracellular fatty acyl‐CoA derivatives and possibly protein acyiation. Preincubation of hepatocytes with moderate concentrations of paimitate (0.5 mM) resulted in a 23% decline in cell‐surface binding and proportional decreases in receptor‐mediated insulin internalization and degradation. Brief pretreatment of hepatocytes with the carnitine palmityltransferase‐I inhibitor, methyl paimoxirate (MP), prevented 70% of the paimitate effects. At higher paimitate concentrations (2.0 mM), cell‐surface binding was reduced by 34%, whereas internalization of the receptor complex was reduced by 78%. These effects were only partially prevented by MP pretreatment. Receptor‐mediated insulin degradation increased by 34% and was uninfluenced by MP pretreatment. Octanoate, which is rapidly shunted into mitochondrial oxidation, produced a dose‐dependent reduction in insulin binding, with proportional decreases in internalization and degradation. Similarly preincubation with 2.0 mM oleate, which, unlike palmitate, is not known to produce protein acylation, resulted in proportional decreases in insulin receptor binding and receptor‐mediated internalization and degradation. High concentrations of octanoate or oleate (2.0 mM) did not reproduce the additive postreceptor effects of palmitate. We conclude that the receptor and post‐receptor effects of moderate palmitate concentrations are closely linked to accelerated fatty acid oxidation. The post‐receptor effects observed at higher concentrations involve other mechanisms, possibly relating to intracellular levels of palmityl‐CoA derivatives. 1993 North American Association for the Study of Obesity (NAASO)

Original languageEnglish (US)
Pages (from-to)18-28
Number of pages11
JournalObesity research
Volume1
Issue number1
DOIs
StatePublished - Jan 1993

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Food Science
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Public Health, Environmental and Occupational Health

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