Alterations in Hepatic Metabolism in fld Mice Reveal a Role for Lipin 1 in Regulating VLDL-Triacylglyceride Secretion
| Autor: | Zhouji Chen, Matthew C. Gropler, John C. Lawrence, Jin Norris, Brian N. Finck, Thurl E. Harris |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Transcriptional Activation medicine.medical_specialty Very low-density lipoprotein Time Factors Amino Acid Motifs Phosphatidate Phosphatase Peroxisome proliferator-activated receptor Lipoproteins VLDL Biology Article Mice chemistry.chemical_compound Transduction Genetic Internal medicine medicine Animals PPAR alpha Secretion Obesity Cells Cultured Triglycerides Mice Knockout chemistry.chemical_classification Mice Inbred BALB C Fatty acid metabolism Nuclear Proteins Metabolism Phosphatidate phosphatase Protein Structure Tertiary Mice Inbred C57BL Disease Models Animal Cytosol Endocrinology Liver chemistry Mutagenesis Site-Directed Insulin Resistance Signal transduction Apolipoprotein B-48 Carrier Proteins Cardiology and Cardiovascular Medicine Stearoyl-CoA Desaturase Signal Transduction |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 28:1738-1744 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | 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. Methods and 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. |
| Databáze: | OpenAIRE |
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