Receptor and postreceptor effects of free fatty acids (FFA) on hepatocyte insulin dynamics

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

Research output: Contribution to journalArticle

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Abstract

The effects of free fatty acids (FFA) on insulin receptor binding and processing (internalization, degradation, dissociation, and release) were examined in hepatocytes isolated from 12-week-old female rats. Animals were fasted for 24 h to deplete liver glycogen and lipid content. Cells were preincubated for 30 min or 3 h at 37°C in media containing 10 mM lactate, 1 mM pyruvate, and 3.5 percent albumin with increasing concentrations of palmitate (0.00, 0.05, 0.2, 0.5, 1.0 and 2.0 mM). Under these conditions palmitate is the primary substrate for cellular metabolism, and its major fate is oxidation. Equilibrium binding was determined after 18-20 h of incubation at 4 °C with radiolabeled insulin and increasing concentrations of unlabeled hormone. With increasing palmitate concentration, a dose-dependent decline in cell-surface insulin receptor binding was observed. Binding decreased by 35 percent and 44 percent after 30 min and 3 h of preincubation with 2 mM palmitate, respectively. This decrease was due to a reduction in insulin receptor number. Receptor-mediated insulin processing was evaluated in cells prelabeled at 4 °C with 125I (A14)-monoiodoinsulin at an insulin concentration of 100 pM and reincubated at 37 °C for up to 30 min. The amount of internalized insulin was decreased by preincubation of hepatocytes with palmitate. This decrease was proportional to the reduction in cell-surface insulin receptor density at palmitate concentrations of 0.05-0.5 mM, but was disproportionally greater at higher fatty acid concentrations. Receptor-mediated insulin degradation decreased at palmitate concentrations between 0.05 and 1.0 mM. At 2 mM, however, insulin degradation was enhanced. This enhancement was observed after 30 min or 3 h of exposure to the fatty acid. Dissociation and/or release of cell-associated internalized insulin was not influenced by the FFA exposure. The effects of FFA on hepatocyte insulin binding and processing were contingent upon cellular metabolism, since no changes were noted when cells were preincubated with palmitate at 4 °C under otherwise similar conditions. Thus the in vitro exposure of hepatocytes to FFA influences both receptor and postreceptor events mediating insulin metabolism. These effects may account for the altered hepatic insulin extraction and sensitivity that accompany abdominal obesity and its progression to diabetes.

Original languageEnglish (US)
Pages (from-to)831-841
Number of pages11
JournalInternational Journal of Obesity
Volume14
Issue number10
StatePublished - 1990

Fingerprint

Palmitates
Nonesterified Fatty Acids
hepatocytes
palmitates
free fatty acids
Hepatocytes
Insulin Receptor
insulin
Insulin
receptors
Cell Surface Receptors
cells
Fatty Acids
metabolism
degradation
Liver Glycogen
Abdominal Obesity
fatty acids
Pyruvic Acid
liver

Keywords

  • body fat distribution
  • FFA
  • hepatocytes
  • insulin metabolism
  • insulin receptor

ASJC Scopus subject areas

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

Cite this

Receptor and postreceptor effects of free fatty acids (FFA) on hepatocyte insulin dynamics. / Hennes, M. M I; Shrago, E.; Kissebah, A. H.

In: International Journal of Obesity, Vol. 14, No. 10, 1990, p. 831-841.

Research output: Contribution to journalArticle

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