Mice with an adipocyte-specific lipin 1 separation-of-function allele reveal unexpected roles for phosphatidic acid in metabolic regulation
| Autor: | Karim Nadra, Mayurranjan S. Mitra, Roman Chrast, Kari T. Chambers, Xiong Su, Hongmei Ren, Zhouji Chen, Brian N. Finck, Samuel Klein, Andrew J. Morris, Thurl E. Harris, Angela M. Hall |
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| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty Lipolysis Blotting Western Phosphatidate Phosphatase Phosphatidic Acids Adipose tissue Biology Real-Time Polymerase Chain Reaction Gas Chromatography-Mass Spectrometry Glycerides Mice chemistry.chemical_compound 3T3-L1 Cells Adipocyte Internal medicine Adipocytes medicine Animals Humans Obesity Cloning Molecular Protein kinase A signaling Protein kinase A Transcription factor Alleles DNA Primers Mice Inbred BALB C Multidisciplinary Nuclear Proteins Phosphatidic acid Biological Sciences Phosphatidate phosphatase Cyclic AMP-Dependent Protein Kinases Cyclic Nucleotide Phosphodiesterases Type 4 Mice Inbred C57BL Endocrinology chemistry Female Metabolic Networks and Pathways |
| Zdroj: | Proceedings of the National Academy of Sciences. 110:642-647 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Lipin 1 is a coregulator of DNA-bound transcription factors and a phosphatidic acid (PA) phosphatase (PAP) enzyme that catalyzes a critical step in the synthesis of glycerophospholipids. Lipin 1 is highly expressed in adipocytes, and constitutive loss of lipin 1 blocks adipocyte differentiation; however, the effects of Lpin1 deficiency in differentiated adipocytes are unknown. Here we report that adipocyte-specific Lpin1 gene recombination unexpectedly resulted in expression of a truncated lipin 1 protein lacking PAP activity but retaining transcriptional regulatory function. Loss of lipin 1-mediated PAP activity in adipocytes led to reduced glyceride synthesis and increased PA content. Characterization of the deficient mice also revealed that lipin 1 normally modulates cAMP-dependent signaling through protein kinase A to control lipolysis by metabolizing PA, which is an allosteric activator of phosphodiesterase 4 and the molecular target of rapamycin. Consistent with these findings, lipin 1 expression was significantly related to adipose tissue lipolytic rates and protein kinase A signaling in adipose tissue of obese human subjects. Taken together, our findings identify lipin 1 as a reciprocal regulator of triglyceride synthesis and hydrolysis in adipocytes, and suggest that regulation of lipolysis by lipin 1 is mediated by PA-dependent modulation of phosphodiesterase 4. |
| Databáze: | OpenAIRE |
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