Alterations in hepatic metabolism in fld mice reveal a role for lipin 1 in regulating VLDL-triacylglyceride secretion.
OBJECTIVE
Lipin 1 controls fatty acid metabolism in the nucleus as a transcriptional regulator and in the cytosol as an enzyme catalyzing the penultimate step in phosphoglycerol triacylglyceride (TAG) synthesis. We sought to evaluate the effects of lipin 1 on hepatic TAG synthesis and secretion by gain-of-function and loss-of-function approaches.


RESULTS
Rates of TAG synthesis were not impaired in hepatocytes isolated from adult lipin 1-deficient (fld) mice and were actually increased in 14-day-old fld mice. Additionally, compared to littermate controls, VLDL-TAG secretion rates were markedly increased in fld mice of both ages. Lipin 1 overexpression did not alter TAG synthesis rates but significantly suppressed VLDL-TAG secretion. The lipin 1-mediated suppression of VLDL-TAG secretion was linked to the peptide motif mediating its transcriptional-regulatory effects. However, the expression of candidate genes required for VLDL assembly and secretion was unaltered by lipin 1 activation or deficiency. Finally, the hepatic expression of lipin 1 was diminished in obese insulin-resistant mice, whereas adenoviral-mediated overexpression of lipin 1 in liver of these mice inhibits VLDL-TAG secretion and improves hepatic insulin signaling.


CONCLUSIONS
Collectively, these studies reveal new and unexpected effects of lipin 1 on hepatic TAG metabolism and obesity-related hepatic insulin resistance.
Chen
Zhouji
Z
Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St Louis, MO 63110, USA.
Gropler
Matthew C
MC
Norris
Jin
J
Lawrence
John C
JC
Harris
Thurl E
TE
Finck
Brian N
BN
D020816:Amino Acid Motifs; D000818:Animals; D053283:Apolipoprotein B-48 / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007333:Insulin Resistance; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D014161:Transduction, Genetic; D014280:Triglycerides / Q000378:metabolism*
D053283:Apolipoprotein B-48; D002352:Carrier Proteins; D008079:Lipoproteins, VLDL; D009687:Nuclear Proteins; D047493:PPAR alpha; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C030106:very low density lipoprotein triglyceride; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase