Altered glucocorticoid receptor signaling leading to MASLD progression via reduced very low-density lipoprotein export-associated endoplasmic reticulum stress

You Song¹, Jorke H. Kamstra², Matej Oresic^3,4

¹ Norwegian Institute for Water Research, Økernveien 94, Oslo, Norway

² Utrecht University, Institute for Risk Assessment Sciences (IRAS), Utrecht, the Netherlands

³ Örebro University, School of Medical Sciences, Örebro, Sweden

⁴ University of Turku, Turku Bioscience Centre, Turku, Finland

Acknowledgement: This project was supported by the “Investigation of endocrine-disrupting chemicals as contributors to progression of metabolic dysfunction-associated steatotic liver disease” (EDC-MASLD) consortium funded by the Horizon Europe Program of the European Union (Grant Agreement 101136259). 

This adverse outcome pathway (AOP) describes a mechanistic sequence linking altered glucocorticoid receptor (GR) signaling to the progression of metabolic dysfunction–associated steatotic liver disease (MASLD) through impaired hepatic very-low-density lipoprotein (VLDL) export and subsequent endoplasmic reticulum (ER) stress. Disruption of GR signaling reduces VLDL assembly and secretion, leading to intrahepatic lipid retention and hepatocellular lipotoxicity. Accumulation of lipids within the ER overwhelms protein and lipid handling capacity, inducing ER stress and maladaptive unfolded protein response signaling. Sustained ER stress promotes hepatocyte injury, inflammatory activation, and profibrotic signaling, including TGF-β–mediated hepatic stellate cell activation. These processes drive disease progression from steatosis to steatohepatitis (MASH), fibrosis, and ultimately cirrhosis. This AOP provides a biologically plausible and regulatory-relevant framework for identifying endocrine-disrupting chemicals (EDCs) that promote MASLD progression through GR-mediated disruption of hepatic lipid export and ER homeostasis.

Efficient export of triglycerides via VLDL is essential for maintaining hepatocellular lipid balance and preventing intracellular lipid overload. Impairment of VLDL assembly or secretion results in lipid accumulation within hepatocytes, particularly within the endoplasmic reticulum, where lipoprotein assembly occurs. This accumulation can directly disrupt ER membrane integrity and protein folding capacity, leading to ER stress.

Glucocorticoid receptor (GR) signaling regulates multiple aspects of hepatic lipid metabolism, including lipoprotein assembly, apolipoprotein expression, and triglyceride trafficking. Altered GR signaling—whether through dysregulation or chemical interference—can suppress VLDL export independently of changes in lipid influx or insulin sensitivity. This AOP was developed to capture ER stress as a direct consequence of impaired lipid export, providing a mechanistically distinct pathway linking GR disruption to MASLD progression.

This AOP was developed using an expert-driven conceptual framework supported by targeted literature evaluation across endocrinology, hepatic lipid metabolism, ER stress biology, and chronic liver disease. Initial scoping identified reduced VLDL export as a key mechanistic driver of ER stress and downstream liver injury.

Focused literature searches were conducted to identify evidence supporting:

• GR regulation of VLDL assembly and secretion

• Effects of impaired VLDL export on hepatic lipid retention

• Induction of ER stress by intracellular lipid accumulation

• ER stress–mediated hepatocyte injury and inflammatory signaling

• Fibrogenic pathways involving TGF-β signaling and hepatic stellate cell activation

Evidence from human clinical studies, animal models, and mechanistic in vitro systems was prioritized, with emphasis on chronic perturbations relevant to endocrine disruption.

This AOP is biologically plausible and supported by moderate to strong empirical evidence linking impaired hepatic lipid export to ER stress and progressive liver injury. The sequence of key events reflects conserved cellular stress responses and fibrogenic mechanisms observed across mammalian species.

The AOP is particularly well suited for hazard identification and prioritization of chemicals that disrupt GR-regulated lipid handling without necessarily inducing insulin resistance or increased lipid influx. It complements other GR-mediated MASLD AOPs by highlighting ER stress as a downstream consequence of defective VLDL export.

This AOP may support:

• Identification of GR-modulating chemicals that impair hepatic lipid export

• Integration of ER stress endpoints into MASLD-relevant testing strategies

• Complementary assessment of ER-centric mechanisms alongside mitochondrial stress pathways

• Construction of AOP networks capturing convergent routes to MASLD progression