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Published on: March 11, 2017
Keap1/Nrf2 pathway activation leads to a repressed hepatic gluconeogenic and lipogenic program in mice on a high-fat
Stephen L Slocum1, John J Skoko2, Nobunao Wakabayashi2
1Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA.
Abstract:
The Keap1/Nrf2 pathway, known to regulate the expression of a series of cytoprotective and antioxidant genes, has been studied in the context of obesity and type 2 diabetes; diseases that are characterized by chronic oxidative stress. There is increasing evidence, however, that the transcription factor Nrf2 can crosstalk with pathways not directly related to cytoprotection. Our present work focuses on the effect of Nrf2 on hepatic gluconeogenesis and lipogenesis, two metabolic processes which are dysregulated in the obese/diabetic state. To this end, a genetic mouse model of Nrf2 pathway activation was used (Keap1-hypo; both Keap1 alleles are hypomorphic) and was exposed to a 3-month high-fat diet along with the relevant control wild-type mice. The Keap1-hypo mice were partially protected from obesity, had lower fasting glucose and insulin levels and developed less liver steatosis compared to the wild-type. Key gluconeogenic and lipogenic enzymes were repressed in the Keap1-hypo livers with concomitant activated Ampk signaling. Primary Keap1-hypo hepatocyte cultures also show increased Ampk signaling and repressed glucose production. In conclusion, increased Keap1/Nrf2 signaling in the liver is accompanied by repressed gluconeogenesis and lipogenesis that can, at least partially, explain the ameliorated diabetic phenotype in the Keap1-hypo mice.
Insights
Activating the Keap1/Nrf2 pathway in the liver protected mice from obesity and type 2 diabetes. This pathway reduced glucose and fat production, offering a potential therapeutic strategy for metabolic diseases.
Area of Science:
- Metabolic diseases
- Molecular biology
- Cellular signaling
Background:
- The Keap1/Nrf2 pathway regulates antioxidant genes and is implicated in obesity and type 2 diabetes.
- Oxidative stress is a hallmark of obesity and type 2 diabetes.
- Nrf2 may influence metabolic pathways beyond cytoprotection.
Purpose of the Study:
- To investigate the role of the Keap1/Nrf2 pathway in hepatic gluconeogenesis and lipogenesis.
- To determine the effects of Nrf2 activation on metabolic dysregulation in obesity and type 2 diabetes.
Main Methods:
- Utilized a genetic mouse model with activated Keap1/Nrf2 signaling (Keap1-hypo).
- Exposed Keap1-hypo and wild-type mice to a 3-month high-fat diet.
- Analyzed metabolic parameters, liver steatosis, key enzyme expression, and AMPK signaling in liver tissues and primary hepatocytes.
Main Results:
- Keap1-hypo mice showed partial protection against obesity, lower fasting glucose and insulin levels, and reduced liver steatosis compared to controls.
- Hepatic gluconeogenic and lipogenic enzymes were repressed in Keap1-hypo mice.
- Increased AMPK signaling and repressed glucose production were observed in Keap1-hypo hepatocytes.
Conclusions:
- Enhanced Keap1/Nrf2 signaling in the liver represses gluconeogenesis and lipogenesis.
- This repression contributes to the ameliorated diabetic phenotype observed in Keap1-hypo mice.
- The Keap1/Nrf2 pathway represents a potential therapeutic target for managing metabolic disorders.
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