Hypoxia via ERK Signaling Inhibits Hepatic PPARα to Promote Fatty Liver.

Abstract

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.

• Authors: Raja Gopal Reddy Mooli, Jessica Rodriguez, Shogo Takahashi, Sumeet Solanki, Frank J Gonzalez, Sadeesh K Ramakrishnan, Yatrik M Shah
• Journal: Cellular and molecular gastroenterology and hepatology (Cell Mol Gastroenterol Hepatol) Vol. 12 Issue 2 Pg. 585-597 ( 2021) ISSN: 2352-345X [Electronic] United States
• PMID: 33798787 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Fatty Acids
• PPAR alpha
• RNA, Messenger
• Cyclic AMP-Dependent Protein Kinases
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Autophagy
• Cells, Cultured
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Fatty Acids (metabolism)
• Fatty Liver (genetics, pathology)
• Feeding Behavior
• Gene Expression Regulation
• Hepatocytes (metabolism)
• Hypoxia (enzymology)
• Lipid Metabolism
• Liver (metabolism)
• MAP Kinase Signaling System
• Mice, Knockout
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Oxidation-Reduction
• PPAR alpha (metabolism)
• Postprandial Period
• RNA, Messenger (genetics, metabolism)
• Mice