Free fatty acids inhibit protein tyrosine phosphatase 1B and activate Akt

Our plain-English summary of Free fatty acids inhibit protein tyrosine phosphatase 1B and activate Akt, by E. Shibata, T. Kanno, A. Tsuchiya, et al (Cellular Physiology and Biochemistry, 2013).

The study

• Authors: E. Shibata, T. Kanno, A. Tsuchiya, K. Kuribayashi, C. Tabata, T. Nakano, T. Nishizaki
• Journal: Cellular Physiology and Biochemistry
• Published: 2013;32(4):871-9
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background/aims: Accumulating evidence has suggested that free fatty acids (FFAs) interact with protein kinases and protein phosphatases. The present study examined the effect of FFAs on protein phosphatases and Akt.

Methods: Activities of protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A), and protein tyrosine phosphatase 1B (PTP1B) were assayed under the cell-free conditions. Phosphorylation of Akt was monitored in MSTO-211H human malignant pleural mesothelioma cells without and with knocking-down phosphatidylinositol 3 kinase (PI3K) or 3-phosphoinositide-dependent protein kinase-1 (PDK1).

Results: In the cell-free assay, unsaturated FFAs (uFFAs) such as oleic, linoleic and linolenic acid and saturated FFAs (sFFAs) such as stearic, palmitic, myristic, and behenic acid markedly reduced PTP1B activity, with the potential for uFFAs greater than that for sFFAs. All the investigated sFFAs inhibited PP2A activity, but otherwise no inhibition was obtained with uFFAs. Both uFFAs and sFFAs had no effect on PP1 activity. Oleic acid phosphorylated Akt both on Thr308 and Ser473, while stearic acid phosphorylated Akt on Thr308 alone. The effects of oleic and stearic acid on Akt phosphorylation were abrogated by the PI3K inhibitor wortmannin or the PDK1 inhibitor BX912 and also by knocking-down PI3K or PDK1.

Conclusion: The results of the present study indicate that uFFAs and sFFAs could activate Akt through a pathway along a PI3K/PDK1/Akt axis in association with PTP1B inhibition.

© 2013 S. Karger AG, Basel

In plain English

This laboratory study did not examine asbestos or people. It tested several free fatty acids on three phosphate-removing enzymes (PP1, PP2A and PTP1B) in cell-free assays, and on a signaling protein called Akt in MSTO-211H human malignant pleural mesothelioma cells. At 10 µM, the unsaturated fatty acids oleic, linoleic and linolenic acid reduced PTP1B activity to 6, 9 and 6% of basal levels. The saturated fatty acids myristic, palmitic, stearic and behenic acid reduced it to 48, 47, 8 and 44%. Only the saturated fatty acids reduced PP2A activity, and none had a significant effect on PP1. In the cells, oleic acid (30 µM) added phosphate to Akt at two sites, Thr308 and Ser473, while stearic acid did so only at Thr308. Drugs or gene silencing that blocked the proteins PI3K or PDK1 stopped both effects. Results came from four independent experiments each. The authors concluded that these fatty acids could activate Akt through a PI3K/PDK1/Akt pathway in association with PTP1B inhibition. They also suggested that fatty acids may promote progression of malignant pleural mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experiment: cell-free enzyme assays plus experiments in a cultured human cancer cell line (using inhibitors, gene silencing by siRNA, and Western blotting)
• Who was studied: No human subjects. Purified human recombinant enzymes (PP1, PP2A, PTP1B) and the MSTO-211H human malignant pleural mesothelioma cell line, obtained from the American Type Culture Collection. Each graph was based on 4 independent experiments.
• Exposure: Free fatty acids, not asbestos. In the enzyme assays, the unsaturated fatty acids oleic, linoleic and linolenic acid and the saturated fatty acids myristic, palmitic, stearic and behenic acid were each used at 10 µM. In the cells, oleic or stearic acid was used at 30 µM for 10 to 30 minutes, with and without the PI3K inhibitor wortmannin (20 nM) or the PDK1 inhibitor BX912 (100 nM).
• Main results:
  • In the cell-free PTP1B assay, oleic, linoleic and linolenic acid (10 µM) reduced PTP1B activity to 6, 9 and 6% of basal levels.
  • In the cell-free PTP1B assay, myristic, palmitic, stearic and behenic acid (10 µM) reduced PTP1B activity to 48, 47, 8 and 44% of basal levels.
  • Stearic, palmitic, myristic and behenic acid (10 µM) significantly reduced PP2A activity to 65, 38, 82 and 42% of basal levels, respectively. The unsaturated fatty acids had no effect on PP2A.
  • Neither the unsaturated nor the saturated fatty acids had a significant effect on PP1 activity.
  • In MSTO-211H cells, oleic acid (30 µM) phosphorylated Akt at Thr308 and Ser473, peaking at 20 minutes of treatment.
  • In MSTO-211H cells, stearic acid (30 µM) phosphorylated Akt only at Thr308.
  • Akt phosphorylation caused by oleic and by stearic acid was abolished by the PI3K inhibitor wortmannin or the PDK1 inhibitor BX912.
  • Akt phosphorylation caused by oleic and by stearic acid was also abolished by silencing PI3K or PDK1 with siRNA.
• The authors' conclusion: The authors concluded that unsaturated and saturated free fatty acids could activate Akt through a PI3K/PDK1/Akt pathway in association with PTP1B inhibition. They also suggested that PP2A inhibition by saturated fatty acids might contribute by preventing Akt dephosphorylation. In the discussion, partly drawing on unpublished data and other studies, they suggested that fatty acids may promote progression of malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors stated that it remains to be answered why oleic acid phosphorylated Akt at Ser473 while stearic acid did not, and that further experiments were under way.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma.

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