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Cited by 195Liver Disease Diagnosis and TreatmentDiet, Metabolism, and DiseaseMetabolism, Diabetes, and Cancer

Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-δ

Lam, Tony K. T., Yoshii, Hidenori, Haber, C. Andrew, Bogdanovic, Elena, Lam, Loretta, Fantus, I. George, Giacca, Adria·2002·American Journal of Physiology-Endocrinology and Metabolism
DOI 10.1152/ajpendo.00038.2002
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Abstract

The mechanisms of the impairment in hepatic glucose metabolism induced by free fatty acids (FFAs) and the importance of FFA oxidation in these mechanisms remain unclear. FFA-induced peripheral insulin resistance has been linked to membrane translocation of novel protein kinase C (PKC) isoforms, but the role of PKC in hepatic insulin resistance has not been assessed. To investigate the biochemical pathways that are induced by FFA in the liver and their relation to glucose metabolism in vivo, we determined endogenous glucose production (EGP), the hepatic content of citrate (product of acetyl-CoA derived from FFA oxidation and oxaloacetate), and hepatic PKC isoform translocation after 2 and 7 h Intralipid + heparin (IH) or SAL in rats. Experiments were performed in the basal state and during hyperinsulinemic clamps (insulin infusion rate, 5 mU · kg−1· min−1). IH increased EGP in the basal state ( P < 0.001) and during hyperinsulinemia ( P < 0.001) at 2 and 7 h. Also, 7-h infusion of IH induced resistance to the suppressive effect of insulin on EGP ( P < 0.05). Glycerol infusion (resulting in plasma glycerol levels similar to IH infusion) did not have any effect on EGP. IH increased hepatic citrate content by twofold, independent of the insulin levels and the duration of IH infusion. IH induced hepatic PKC-δ translocation from the cytosolic to membrane fraction in all groups. PKC-δ translocation was greater at 7 compared with 2 h ( P < 0.05). In conclusion, 1) increased FFA oxidation may contribute to the FFA-induced increase in EGP in the basal state and during hyperinsulinemia but is not associated with FFA-induced hepatic insulin resistance, and 2) the progressive insulin resistance induced by FFA in the liver is associated with a progressive increase in hepatic PKC-δ translocation.

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  • Increased intramyocellular levels of fat metabolites such as FACoA and DAG, which are strong PKC activators, have been demonstrated after lipid infusion.

    “increased intramyocellar levels of fat metabolites, for example, FACoA and DAG, which are strong activators of protein kinase C, have been demonstrated following lipid infusion [176].”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [176]

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Authors
Lam, T. K. T., Yoshii, H., Haber, C. A., Bogdanovic, E., Lam, L., Fantus, I. G., & Giacca, A.
Affiliations
  • Departments of Physiology and
  • University of Toronto (CA)
ORCID
Venue
American Journal of Physiology-Endocrinology and Metabolism
Publisher
American Physiological Society
Published
2002-10-01
Volume
283
Issue
4
Pages
E682-E691
ISSN
  • 0193-1849 (ISSN-L)
  • 1522-1555
DOI
10.1152/ajpendo.00038.2002
OpenAlex
W2042144976
Cited by
195
References
54
Citations by year
2026: 3 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 7 · 2017: 3 · 2016: 5 · 2015: 10 · 2014: 5 · 2013: 9 · 2012: 9
FWCI
9.30
Type
journal article
Language
en
Open access
closed
Locations
  • American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
free fatty acids, hepatic insulin resistance, protein kinase C delta, endogenous glucose production, fatty acid oxidation, hyperinsulinemic-euglycemic clamp, Intralipid, heparin, glycerol infusion, hepatic glucose metabolism
MeSH terms
Animals, Blood Glucose, C-Peptide, Fatty Acids, Nonesterified, Female, Glycerol, Insulin Resistance, Isoenzymes, Liver, Oxidation-Reduction, Protein Kinase C, Triglycerides, Glucose Clamp Technique, Rats, Wistar, Rats, Protein Kinase C-delta

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