Altered glucocorticoid receptor signaling leading to MASLD progression via reduced VLDL export-associated mitochondrial dysfunction

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 suppression of hepatic de novo lipogenesis (DNL) and subsequent mitochondrial dysfunction. Disruption of GR signaling reduces coordinated lipogenic and lipid-buffering pathways in hepatocytes, impairing the safe esterification and storage of fatty acids. This imbalance promotes hepatocellular lipotoxicity, mitochondrial dysfunction, oxidative stress, and hepatocyte injury, triggering inflammatory and fibrogenic responses. Activation of Kupffer cells, hepatic stellate cells, and TGF-β signaling drives extracellular matrix deposition and fibrotic remodeling, ultimately leading to steatohepatitis (MASH), fibrosis, and cirrhosis. This AOP provides a biologically plausible and complementary framework to support the identification and prioritization of endocrine-disrupting chemicals (EDCs) that interfere with GR-regulated lipid homeostasis and contribute to MASLD progression.

While increased de novo lipogenesis is commonly associated with hepatic steatosis, emerging evidence indicates that suppression of lipogenic pathways can also exacerbate liver injury by limiting the hepatocyte’s capacity to safely process and store fatty acids. De novo lipogenesis contributes not only to triglyceride synthesis but also to lipid remodeling and buffering processes that protect against lipotoxic species accumulation.

Glucocorticoid receptor (GR) signaling regulates key transcriptional programs involved in hepatic lipogenesis, fatty acid handling, and mitochondrial metabolism. Altered GR signaling—due to dysregulation or chemical interference—can reduce DNL, disrupt lipid homeostasis, and shift hepatocytes toward accumulation of toxic lipid intermediates. This AOP was developed to capture this less intuitive but mechanistically important route linking altered GR signaling to MASLD progression.

The AOP was developed through expert-driven pathway conceptualization supported by targeted literature evaluation in the areas of endocrine regulation, hepatic lipid metabolism, and chronic liver disease. Initial scoping identified reduced DNL as a plausible upstream disturbance capable of promoting hepatocellular lipotoxicity independent of increased lipid influx.

Focused literature searches were conducted to identify evidence supporting:

• GR regulation of hepatic lipogenic gene networks

• Consequences of suppressed DNL on lipid buffering and toxicity

• Links between lipotoxicity, mitochondrial dysfunction, and oxidative stress

• Inflammatory and fibrogenic signaling driving disease progression

Evidence from human clinical studies, animal models, and mechanistic in vitro systems was evaluated for biological plausibility, consistency, and relevance to regulatory toxicology, particularly in the context of chronic, low-dose chemical exposure.

This AOP is biologically plausible and supported by moderate to strong empirical evidence demonstrating that impaired lipogenic capacity can exacerbate lipotoxic stress and liver injury. The sequence of events reflects conserved cellular stress responses and fibrogenic mechanisms observed across mammalian species.

The AOP is particularly relevant for hazard identification and prioritization of chemicals that interfere with GR signaling and hepatic lipid homeostasis but may not induce classical steatogenic responses. While quantitative understanding across the full pathway is limited, the overall weight of evidence supports its inclusion within an AOP network describing GR-mediated MASLD progression.

This AOP may support:

• Identification of GR-modulating chemicals that disrupt hepatic lipid buffering

• Complementary assessment of non-steatogenic mechanisms contributing to MASLD

• Development of integrated testing strategies incorporating lipid handling and mitochondrial endpoints

• AOP network construction capturing multiple GR-mediated routes to MASLD progression