p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis.
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.
Xiong
Yan
Y
Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709; Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078 Hunan, China.
Collins
Qu Fan
QF
Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709.
An
Jie
J
The Sarah W. Stedman Center for Nutrition and Metabolism, School of Pharmaceutical Sciences, Central South University, Changsha, 410078 Hunan, China.
Lupo
Edgar
E
Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709.
Liu
Hui-Yu
HY
Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709.
Liu
Delong
D
Center for Integrated Genomics, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709.
Robidoux
Jacques
J
Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709.
Liu
Zhenqi
Z
Division of Endocrinology, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, and.
Cao
Wenhong
W
Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709; Division of Endocrinology, Department of Internal Medicine, Duke University, Medical Center, Durham, North Carolina 27710. Electronic address: wcao@thehamner.org.
D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004122:Dimethylallyltranstransferase / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005215:Fasting / Q000097:blood; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005934:Glucagon / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000201:enzymology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D005227:Fatty Acids; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; D005934:Glucagon; D003577:Cytochrome P-450 Enzyme System; D006903:Hydroxymethylglutaryl CoA Reductases; D064429:Fatty Acid Synthases; D004122:Dimethylallyltranstransferase; D048051:p38 Mitogen-Activated Protein Kinases