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

15 Citations (Scopus)

Abstract

We determined whether the palmitate effects on hepatocyte insulin receptor binding and post-receptor trafficking were mediated by accelerated mitochondrial beta-oxidation or accumulation of intracellular fatty acyl-CoA derivatives and possibly protein acylation. Preincubation of hepatocytes with moderate concentrations of palmitate (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 palmoxirate (MP), prevented 70% of the palmitate effects. At higher palmitate 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 post-receptor 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.

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

Fingerprint

Palmitates
Insulin Receptor
Nonesterified Fatty Acids
hepatocytes
palmitates
free fatty acids
Hepatocytes
receptors
Acylation
Oleic Acid
acylation
beta oxidation
insulin
degradation
pretreatment
Palmitoyl Coenzyme A
oleic acid
Acyl Coenzyme A
chemical derivatives
Carnitine

ASJC Scopus subject areas

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

Cite this

Mechanism of free fatty acid effects on hepatocyte insulin receptor binding and processing. / Hennes, M. M.; Shrago, E.; Kissebah, A. H.

In: Obesity research., Vol. 1, No. 1, 01.1993, p. 18-28.

Research output: Contribution to journalArticle

@article{4a6ecc50a0bb47319f21e7b33ba41f39,
title = "Mechanism of free fatty acid effects on hepatocyte insulin receptor binding and processing.",
abstract = "We determined whether the palmitate effects on hepatocyte insulin receptor binding and post-receptor trafficking were mediated by accelerated mitochondrial beta-oxidation or accumulation of intracellular fatty acyl-CoA derivatives and possibly protein acylation. Preincubation of hepatocytes with moderate concentrations of palmitate (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 palmoxirate (MP), prevented 70{\%} of the palmitate effects. At higher palmitate 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 post-receptor 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.",
author = "Hennes, {M. M.} and E. Shrago and Kissebah, {A. H.}",
year = "1993",
month = "1",
language = "English (US)",
volume = "1",
pages = "18--28",
journal = "Obesity",
issn = "1930-7381",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Mechanism of free fatty acid effects on hepatocyte insulin receptor binding and processing.

AU - Hennes, M. M.

AU - Shrago, E.

AU - Kissebah, A. H.

PY - 1993/1

Y1 - 1993/1

N2 - We determined whether the palmitate effects on hepatocyte insulin receptor binding and post-receptor trafficking were mediated by accelerated mitochondrial beta-oxidation or accumulation of intracellular fatty acyl-CoA derivatives and possibly protein acylation. Preincubation of hepatocytes with moderate concentrations of palmitate (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 palmoxirate (MP), prevented 70% of the palmitate effects. At higher palmitate 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 post-receptor 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.

AB - We determined whether the palmitate effects on hepatocyte insulin receptor binding and post-receptor trafficking were mediated by accelerated mitochondrial beta-oxidation or accumulation of intracellular fatty acyl-CoA derivatives and possibly protein acylation. Preincubation of hepatocytes with moderate concentrations of palmitate (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 palmoxirate (MP), prevented 70% of the palmitate effects. At higher palmitate 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 post-receptor 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.

UR - http://www.scopus.com/inward/record.url?scp=0003144527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0003144527&partnerID=8YFLogxK

M3 - Article

VL - 1

SP - 18

EP - 28

JO - Obesity

JF - Obesity

SN - 1930-7381

IS - 1

ER -