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p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis
- Source :
- The Journal of biological chemistry. 282(7)
- Publication Year :
- 2006
-
Abstract
- Hepatic lipogenesis is the principal route to convert excess carbohydrates into fatty acids and is mainly regulated by two opposing hormones, insulin and glucagon. Although insulin stimulates hepatic lipogenesis, glucagon inhibits it. However, the mechanism by which glucagon suppresses lipogenesis remains poorly understood. In this study, we have observed that p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. Levels of plasma triglyceride and triglyceride accumulation in the liver were both elevated when p38 activation was blocked. Expression levels of central lipogenic genes, including sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase, hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl pyrophosphate synthase, and cytochrome P-450-51, were decreased in liver by fasting and in primary hepatocytes by glucagon but increased by the inhibition of p38. In addition, we have shown that p38 can inhibit insulin-induced expression of key lipogenic genes in isolated hepatocytes. Our results in hepatoma cells demonstrate that p38 plays an inhibitory role in the activation of the SREBP-1c promoter. Finally, we have shown that transcription of the PGC-1beta gene, a key coactivator of SREBP-1c, was reduced in liver by fasting and in isolated hepatocytes by glucagon. This reduction was significantly reversed by the blockade of p38. Insulin-induced expression of the PGC-1beta gene was enhanced by the inhibition of p38 but suppressed by the activation of p38. Together, we have identified an inhibitory role for p38 in the transcription of central lipogenic genes, SREBPs, and PGC-1beta and hepatic lipogenesis.
- Subjects :
- medicine.medical_specialty
medicine.medical_treatment
Coenzyme A
Farnesyl pyrophosphate
Biology
Biochemistry
Glucagon
p38 Mitogen-Activated Protein Kinases
chemistry.chemical_compound
Mice
Cytochrome P-450 Enzyme System
Internal medicine
Cell Line, Tumor
Coactivator
medicine
Animals
Insulin
Protein kinase A
Molecular Biology
Triglycerides
Fatty Acids
Cell Biology
Fasting
Dimethylallyltranstransferase
Lipid Metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Enzyme Activation
Fatty acid synthase
Endocrinology
chemistry
Gene Expression Regulation
Liver
Lipogenesis
biology.protein
Hepatocytes
Trans-Activators
Carbohydrate Metabolism
Hydroxymethylglutaryl CoA Reductases
Fatty Acid Synthases
Sterol Regulatory Element Binding Protein 1
Transcription Factors
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 282
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....4db81d58c8807780277d8ee58871897d