Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol.

Abstract

Although an elevated triacylglycerol content in non-adipose tissues is often associated with insulin resistance, the mechanistic relationship remains unclear. The data support roles for intermediates in the glycerol-3-phosphate pathway of triacylglycerol synthesis: diacylglycerol (DAG), which may cause insulin resistance in liver by activating PKCϵ, and phosphatidic acid (PA), which inhibits insulin action in hepatocytes by disrupting the assembly of mTOR and rictor. To determine whether increases in DAG and PA impair insulin signaling when produced by pathways other than that of de novo synthesis, we examined primary mouse hepatocytes after enzymatically manipulating the cellular content of DAG or PA. Overexpressing phospholipase D1 or phospholipase D2 inhibited insulin signaling and was accompanied by an elevated cellular content of total PA, without a change in total DAG. Overexpression of diacylglycerol kinase-θ inhibited insulin signaling and was accompanied by an elevated cellular content of total PA and a decreased cellular content of total DAG. Overexpressing glycerol-3-phosphate acyltransferase-1 or -4 inhibited insulin signaling and increased the cellular content of both PA and DAG. Insulin signaling impairment caused by overexpression of phospholipase D1/D2 or diacylglycerol kinase-θ was always accompanied by disassociation of mTOR/rictor and reduction of mTORC2 kinase activity. However, although the protein ratio of membrane to cytosolic PKCϵ increased, PKC activity itself was unaltered. These data suggest that PA, but not DAG, is associated with impaired insulin action in mouse hepatocytes.

• Authors: Chongben Zhang, Gwen Hwarng, Daniel E Cooper, Trisha J Grevengoed, James M Eaton, Viswanathan Natarajan, Thurl E Harris, Rosalind A Coleman
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 6 Pg. 3519-28 (Feb 06 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 25512376 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Carrier Proteins
• Diglycerides
• Insulin
• Phosphatidic Acids
• Rapamycin-Insensitive Companion of mTOR Protein
• rictor protein, mouse
• Glycerol-3-Phosphate O-Acyltransferase
• Diacylglycerol Kinase
• TOR Serine-Threonine Kinases
• Protein Kinase C
• phospholipase D2
• Phospholipase D
• phospholipase D1

Topics

• Animals
• Carrier Proteins (metabolism)
• Cells, Cultured
• Diacylglycerol Kinase (genetics, metabolism)
• Diglycerides (metabolism)
• Glycerol-3-Phosphate O-Acyltransferase (genetics, metabolism)
• Hepatocytes (metabolism)
• Insulin (metabolism)
• Mice
• Mice, Inbred C57BL
• Phosphatidic Acids (metabolism)
• Phospholipase D (genetics, metabolism)
• Protein Kinase C (metabolism)
• Rapamycin-Insensitive Companion of mTOR Protein
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)