Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

Joseph S Marino,Lance A Stechschulte,David E Stec,Andrea Nestor-Kalinoski,Sydni Coleman,Terry D Hinds

doi:10.1074/jbc.m116.752311

Abstract

Glucocorticoids (GCs) regulate energy supply in response to stress by increasing hepatic gluconeogenesis during fasting. Long-term GC treatment induces hepatic steatosis and weight gain. GC signaling is coordinated via the GC receptor (GR) GRα, as the GRβ isoform lacks a ligand-binding domain. The roles of the GR isoforms in the regulation of lipid accumulation is unknown. The purpose of this study was to determine whether GRβ inhibits the actions of GCs in the liver, or enhances hepatic lipid accumulation. We show that GRβ expression is increased in adipose and liver tissues in obese high-fat fed mice. Adenovirus-mediated delivery of hepatic GRβ overexpression (GRβ-Ad) resulted in suppression of gluconeogenic genes and hyperglycemia in mice on a regular diet. Furthermore, GRβ-Ad mice had increased hepatic lipid accumulation and serum triglyceride levels possibly due to the activation of NF-κB signaling and increased tumor necrosis factor α (TNFα) and inducible nitric-oxide synthase expression, indicative of enhanced M1 macrophages and the development of steatosis. Consequently, GRβ-Ad mice had increased glycogen synthase kinase 3β (GSK3β) activity and reduced hepatic PPARα and fibroblast growth factor 21 (FGF21) expression and lower serum FGF21 levels, which are two proteins known to increase during fasting to enhance the burning of fat by activating the β-oxidation pathway. In conclusion, GRβ antagonizes the GC-induced signaling during fasting via GRα and the PPARα-FGF21 axis that reduces fat burning. Furthermore, hepatic GRβ increases inflammation, which leads to hepatic lipid accumulation.

Highlights

Glucocorticoids (GCs) regulate energy supply in response to stress by increasing hepatic gluconeogenesis during fasting
non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation that, when coupled with another “hit,” such as increased oxidative stress, insulin resistance, or inflammation can lead to the development of non-alcoholic steatohepatitis (NASH) [1]
GC receptor (GR)␤ Expression Increases in Response to HFD—Acute elevations in GC promote adipose tissue lipolysis and hepatic gluconeogenesis, which is orchestrated by GR␣

Summary

Introduction

Glucocorticoids (GCs) regulate energy supply in response to stress by increasing hepatic gluconeogenesis during fasting. NAFLD is characterized by hepatic fat accumulation that, when coupled with another “hit,” such as increased oxidative stress, insulin resistance, or inflammation can lead to the development of non-alcoholic steatohepatitis (NASH) [1]. GR␤ Increases Lipid Accumulation in Liver mouse with hepatic-specific GR knock-out and delivery of human GR␤-regulated gluconeogenesis and inflammation in liver These studies suggest that GR␤ may have a role in the regulation of hepatic lipid storage and peripheral insulin resistance. Hepatic PPAR␣ increases the fat burning and glucose-lowering hormone, fibroblast growth factor 21 (FGF21), which causes a dramatic decrease in lipid accumulation in whole animals and sensitization to peripheral insulin signaling [12,13,14,15,16,17,18,19]. GR␤ may be involved in the initial phases of the development of NAFLD

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