Opposite Cross-Talk by Oleate and Palmitate on Insulin Signaling in Hepatocytes through Macrophage Activation

• Published in: The Journal of biological chemistry Vol. 290; no. 18; pp. 11663 - 11677
• Main Authors: Pardo, Virginia, González-Rodríguez, Águeda, Guijas, Carlos, Balsinde, Jesús, Valverde, Ángela M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Line; Culture Media, Serum-Free; Cytokine; Cytokines - metabolism; Eicosanoid; Eicosanoids - metabolism; Endoplasmic Reticulum Stress (ER Stress); Endoplasmic Reticulum Stress - drug effects; Enzyme Activation - drug effects; Fatty Acid; Hepatocyte; Hepatocytes - cytology; Hepatocytes - drug effects; Inflammation; Insulin - metabolism; Insulin Resistance; Leukotriene B4 - metabolism; Macrophage; Macrophage Activation - drug effects; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Molecular Bases of Disease; Oleic Acid - pharmacology; Palmitates - pharmacology; Protein Kinases - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Signal Transduction; Signal Transduction - drug effects; Type 2 Diabetes; Hepatocyte; Signal Transduction; Fatty Acid; Eicosanoid; Type 2 Diabetes; Cytokine; Insulin Resistance; Inflammation; Endoplasmic Reticulum Stress (ER Stress); Macrophage
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.649483

Chronic low grade inflammation in adipose tissue during obesity is associated with an impairment of the insulin signaling cascade. In this study, we have evaluated the impact of palmitate or oleate overload of macrophage/Kupffer cells in triggering stress-mediated signaling pathways, in lipoapoptosis, and in the cross-talk with insulin signaling in hepatocytes. RAW 264.7 macrophages or Kupffer cells were stimulated with oleate or palmitate, and levels of M1/M2 polarization markers and the lipidomic profile of eicosanoids were analyzed. Whereas proinflammatory cytokines and total eicosanoids were elevated in macrophages/Kupffer cells stimulated with palmitate, enhanced arginase 1 and lower leukotriene B4 (LTB4) levels were detected in macrophages stimulated with oleate. When hepatocytes were pretreated with conditioned medium (CM) from RAW 264.7 or Kupffer cells loaded with palmitate (CM-P), phosphorylation of stress kinases and endoplasmic reticulum stress signaling was increased, insulin signaling was impaired, and lipoapoptosis was detected. Conversely, enhanced insulin receptor-mediated signaling and reduced levels of the phosphatases protein tyrosine phosphatase 1B (PTP1B) and phosphatase and tensin homolog (PTEN) were found in hepatocytes treated with CM from macrophages stimulated with oleate (CM-O). Supplementation of CM-O with LTB4 suppressed insulin sensitization and increased PTP1B and PTEN. Furthermore, LTB4 decreased insulin receptor tyrosine phosphorylation in hepatocytes, activated the NFκB pathway, and up-regulated PTP1B and PTEN, these effects being mediated by LTB4 receptor BTL1. In conclusion, oleate and palmitate elicit an opposite cross-talk between macrophages/Kupffer cells and hepatocytes. Whereas CM-P interferes at the early steps of insulin signaling, CM-O increases insulin sensitization, possibly by reducing LTB4. Background: Chronic low grade inflammation during obesity is associated with impairments in the insulin signaling cascade. Results: Oleate and palmitate elicit opposite effects in insulin signaling in hepatocytes through macrophage stimulation. Conclusion: An endocrine/paracrine cross-talk between macrophages/Kupffer cells and hepatocytes modulates insulin signaling. Significance: Switching macrophage/Kupffer cell polarization will be of benefit against insulin resistance in the liver.