Saturated fatty acids inhibit hepatic insulin action by modulating insulin receptor expression and post-receptor signalling.

Ruddock, M. W.; Stein, A.; Landaker, E.; Park, J.; Cooksey, R. C.; McClain, D.; Patti, M.-E.

doi:10.1093/jb/mvn105

Cited by 75Metabolism, Diabetes, and CancerCancer, Lipids, and MetabolismLipid metabolism and biosynthesis

Saturated fatty acids inhibit hepatic insulin action by modulating insulin receptor expression and post-receptor signalling.

Ruddock, M. W., Stein, A., Landaker, E., Park, J., Cooksey, R. C., McClain, D., Patti, M.-E.·2008·Journal of Biochemistry

DOI 10.1093/jb/mvn105

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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.

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These effects in the liver appear to be mediated via reduced expression of the insulin receptor.
“These effects in the liver appear to be mediated via reduced expression of the insulin receptor (221).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [221]
Incubation of hepatocytes with saturated long-chain fatty acids induces insulin resistance by reducing insulin-stimulated tyrosine phosphorylation of the insulin receptor and its downstream substrates.
“At a cellular level, incubation of hepatocytes with saturated long-chain fatty acids induces insulin resistance by reducing insulin-stimulated tyrosine phosphorylation of the insulin receptor and its downstream substrates (220, 221).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [221]

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Authors: Ruddock, M. W., Stein, A., Landaker, E., Park, J., Cooksey, R. C., McClain, D., & Patti, M.-E.
Affiliations: Joslin Diabetes Center (US)
Corresponding author: Ruddock, M. W.
ORCID: Ruddock, M. W.
Park, J.
McClain, D.
Patti, M.-E.
Venue: Journal of Biochemistry
Publisher: Oxford University Press (OUP)
Published: 2008-08-11
Volume: 144
Issue: 5
Pages: 599-607
ISSN: 0021-924X (ISSN-L)
DOI: 10.1093/jb/mvn105
OpenAlex: W2046497969
Cited by: 75
References: 54
Citations by year: 2025: 2 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 2 · 2020: 2 · 2019: 2 · 2017: 2 · 2016: 1 · 2015: 9 · 2014: 11 · 2013: 7 · 2012: 5
FWCI: 2.47
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Biochemistry (publishedVersion)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Funders: National Institutes of Health (5k08dk002526-03)
National Institute of Diabetes and Digestive and Kidney Diseases (DK02526, DK-62948, R01DK062948)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords: saturated fatty acids, palmitate, hepatic insulin resistance, insulin receptor expression, insulin receptor tyrosine phosphorylation, insulin receptor substrate 2, Akt phosphorylation, glycogen synthase kinase-3, FOXO1, p70 S6 kinase, fatty acid oxidation, hepatocytes, insulin signaling
MeSH terms: Aminoimidazole Carboxamide, Animals, Enzyme Activation, Enzyme Inhibitors, Epoxy Compounds, Fatty Acids, Fatty Acids, Nonesterified, Carcinoma, Hepatocellular, Hypoglycemic Agents, Insulin, Liver, Liver Neoplasms, Oxidation-Reduction, Phosphorylation, Receptor, Insulin, Ribonucleotides, Triazenes, Signal Transduction, Mice, Knockout, Palmitic Acid, Phosphatidylinositol 3-Kinases, Glycogen Synthase Kinase 3, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, Mice, Rats, Forkhead Transcription Factors, Insulin Receptor Substrate Proteins

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Saturated fatty acids inhibit hepatic insulin action by modulating insulin receptor expression and post-receptor signalling.

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