Altered glucocorticoid receptor signaling leading to MASLD progression via reduced lipogenesis-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 suppression of hepatic de novo lipogenesis (DNL) and subsequent endoplasmic reticulum (ER) stress. Disruption of GR signaling reduces coordinated lipogenic and lipid-buffering pathways, impairing the hepatocyte’s capacity to safely esterify and process fatty acids. This imbalance promotes hepatocellular lipotoxicity and lipid accumulation within the ER, triggering ER stress and maladaptive unfolded protein response signaling. Sustained ER stress leads to hepatocyte injury, inflammatory activation, and profibrotic signaling, including TGF-β–mediated hepatic stellate cell activation. These processes drive progression from steatosis to steatohepatitis (MASH), fibrosis, and 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 buffering and ER homeostasis.

Although increased de novo lipogenesis is frequently associated with hepatic steatosis, adequate lipogenic capacity is also essential for maintaining ER and hepatocyte homeostasis. De novo lipogenesis supports triglyceride synthesis, lipid remodeling, and buffering of excess fatty acids, processes that limit the accumulation of toxic lipid intermediates within the ER. Suppression of DNL can therefore increase susceptibility to lipotoxic stress, particularly under conditions of ongoing lipid exposure.

Glucocorticoid receptor (GR) signaling regulates transcriptional programs involved in hepatic lipogenesis, fatty acid handling, and cellular stress responses. Altered GR signaling—due to dysregulation or chemical interference—can suppress DNL, disrupt ER lipid balance, and promote ER stress. This AOP was developed to capture this mechanistically distinct pathway linking GR perturbation to MASLD progression through ER stress rather than mitochondrial dysfunction.

The AOP was developed using an expert-driven conceptual framework supported by targeted literature evaluation across endocrine signaling, hepatic lipid metabolism, ER stress biology, and chronic liver disease. Initial scoping identified reduced DNL as a plausible upstream disturbance capable of inducing ER stress independently of increased lipid influx or impaired lipid export.

Focused literature searches were conducted to identify evidence supporting:

• GR regulation of hepatic lipogenic gene networks

• Consequences of suppressed DNL on lipid buffering and ER lipid composition

• Induction of ER stress by lipid imbalance and lipotoxic species

• ER stress–mediated hepatocyte injury and inflammatory signaling

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

Evidence from human 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 empirical evidence demonstrating that suppression of hepatic lipogenesis can exacerbate ER stress and promote progressive liver injury. The sequence of key events reflects conserved cellular stress and fibrogenic mechanisms observed across mammalian species.

The AOP is particularly relevant for hazard identification and prioritization of chemicals that interfere with GR-regulated lipid homeostasis but may not induce classical steatogenic or insulin-resistant phenotypes. It complements other GR-mediated MASLD AOPs by highlighting ER stress as a downstream consequence of impaired lipid buffering capacity.

This AOP may support:

• Identification of GR-modulating chemicals that impair hepatic lipid buffering capacity

• Inclusion of ER stress endpoints in MASLD-relevant testing strategies

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

• Construction of AOP networks capturing multiple GR-mediated routes to MASLD progression