Hypoxia via ERK Signaling Inhibits Hepatic PPARα to Promote Fatty Liver
| Autor: | Yatrik M. Shah, Shogo Takahashi, Sadeesh K. Ramakrishnan, Raja Gopal Reddy Mooli, Frank J. Gonzalez, Sumeet Solanki, Jessica Rodriguez |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway HFD high-fat diet Fgf21 fibroblast growth factor 21 β-Oxidation RC799-869 VHL Von Hippel-Lindau PPARα Liver disease 0302 clinical medicine ERK extracellular signal-regulated kinase Cyp4a10 and Cyp4a14 cytochrome P450 family 4 subfamily a polypeptide 10 and 14 Nonalcoholic fatty liver disease Hypoxia Cells Cultured Original Research Mice Knockout chemistry.chemical_classification Chemistry Fatty Acids Fatty liver Gastroenterology Diseases of the digestive system. Gastroenterology Postprandial Period MEK ERK medicine.anatomical_structure Liver CD36 cluster of differenatiation 36 Hepatocyte qPCR quantitative polymerase chain reaction 030211 gastroenterology & hepatology Oxidation-Reduction medicine.medical_specialty MAP Kinase Signaling System Acot1 acyl-CoA thioesterase 1 PPARα peroxisome proliferator activated receptor alpha HIF1α and HIF2α hypoxia inducing factor 1 and 2 alpha 03 medical and health sciences Internal medicine Genetic model Autophagy medicine Animals HIF PPAR alpha RNA Messenger Mitogen-Activated Protein Kinase Kinases Hepatology Cpt1a carnitine palmitoyltransferase 1 Fatty acid Acox1 acyl-coenzyme A oxidase Feeding Behavior Lipid Metabolism medicine.disease WT wild-type Cyclic AMP-Dependent Protein Kinases Fatty Liver 030104 developmental biology Endocrinology Gene Expression Regulation Hepatocytes PKA protein kinase A NAFLD nonalcoholic fatty liver disease Steatosis |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 2, Pp 585-597 (2021) Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2021.03.011 |
| Popis: | Background & Aims Fatty liver or nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with comorbidities such as insulin resistance and cardiovascular and metabolic diseases. Chronic activation of hypoxic signaling, in particular, hypoxia-inducible factor (HIF)2α, promotes NAFLD progression by repressing genes involved in fatty acid β-oxidation through unclear mechanisms. Therefore, we assessed the precise mechanism by which HIF2α promotes fatty liver and its physiological relevance in metabolic homeostasis. Methods Primary hepatocytes from VHL (VhlΔHep) and PPARα (Ppara-null) knockout mice that were loaded with fatty acids, murine dietary protocols to induce hepatic steatosis, and fasting-refeeding dietary regimen approaches were used to test our hypothesis. Results Inhibiting autophagy using chloroquine did not decrease lipid contents in VhlΔHep primary hepatocytes. Inhibition of ERK using MEK inhibitor decreased lipid contents in primary hepatocytes from a genetic model of constitutive HIF activation and primary hepatocytes loaded with free fatty acids. Moreover, MEK-ERK inhibition potentiated ligand-dependent activation of PPARα. We also show that MEK-ERK inhibition improved diet-induced hepatic steatosis, which is associated with the induction of PPARα target genes. During fasting, fatty acid β-oxidation is induced by PPARα, and refeeding inhibits β-oxidation. Our data show that ERK is involved in the post-prandial repression of hepatic PPARα signaling. Conclusions Overall, our results demonstrate that ERK activated by hypoxia signaling plays a crucial role in fatty acid β-oxidation genes by repressing hepatocyte PPARα signaling. Graphical abstract |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|