Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol
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Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol. / Zhang, Chongben; Hwarng, Gwen; Cooper, Daniel E; Grevengoed, Trisha Jean; Eaton, James M; Natarajan, Viswanathan; Harris, Thurl E; Coleman, Rosalind A.
In: The Journal of Biological Chemistry, Vol. 290, No. 6, 06.02.2015, p. 3519-28.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol
AU - Zhang, Chongben
AU - Hwarng, Gwen
AU - Cooper, Daniel E
AU - Grevengoed, Trisha Jean
AU - Eaton, James M
AU - Natarajan, Viswanathan
AU - Harris, Thurl E
AU - Coleman, Rosalind A
N1 - © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2015/2/6
Y1 - 2015/2/6
N2 - 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.
AB - 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.
KW - Animals
KW - Carrier Proteins
KW - Cells, Cultured
KW - Diacylglycerol Kinase
KW - Diglycerides
KW - Glycerol-3-Phosphate O-Acyltransferase
KW - Hepatocytes
KW - Insulin
KW - Mice
KW - Mice, Inbred C57BL
KW - Phosphatidic Acids
KW - Phospholipase D
KW - Protein Kinase C
KW - Signal Transduction
KW - TOR Serine-Threonine Kinases
U2 - 10.1074/jbc.M114.602789
DO - 10.1074/jbc.M114.602789
M3 - Journal article
C2 - 25512376
VL - 290
SP - 3519
EP - 3528
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 6
ER -
ID: 146698672