Altered glucocorticoid receptor signaling leading to MASLD progression via reduced very low-density lipoprotein 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 impaired hepatic very-low-density lipoprotein (VLDL) export and downstream mitochondrial dysfunction. Disruption of GR signaling leads to reduced VLDL assembly and secretion, promoting intrahepatic lipid retention and hepatocellular lipotoxicity. Excess lipid accumulation triggers mitochondrial dysfunction, oxidative stress, hepatocyte injury, and inflammatory activation, followed by profibrotic signaling mediated in part by TGF-β–driven hepatic stellate cell activation. These processes culminate in progressive liver pathology, including steatosis, steatohepatitis (MASH), fibrosis, and cirrhosis. This AOP provides a biologically plausible and regulatory-relevant framework to support the identification and prioritization of endocrine-disrupting chemicals (EDCs) that interfere with GR-regulated lipid handling and contribute to MASLD progression.

Efficient hepatic export of triglycerides via VLDL is a critical protective mechanism preventing excessive lipid accumulation in hepatocytes. Glucocorticoid receptor (GR) signaling plays an important role in regulating lipid metabolism, including pathways involved in lipoprotein assembly, apolipoprotein expression, and triglyceride trafficking. Disruption of GR signaling—through altered activation, impaired transcriptional control, or chemical interference—can reduce VLDL export capacity, leading to hepatic lipid retention even in the absence of increased lipid influx.

This AOP was developed to capture a distinct and mechanistically relevant route by which altered GR signaling promotes MASLD progression, emphasizing impaired lipid export rather than increased lipid supply. The pathway reflects clinical and experimental observations that defects in VLDL secretion contribute to steatosis, lipotoxic stress, mitochondrial dysfunction, and progressive liver injury.

The AOP was constructed using an expert-informed, targeted literature evaluation strategy focused on the intersection of endocrine regulation, hepatic lipid export, and chronic liver disease. Initial scoping identified reduced VLDL export as a key mechanistic node linking GR dysregulation to hepatic steatosis and downstream lipotoxicity.

Focused literature searches were conducted to identify evidence supporting:

• GR regulation of VLDL assembly and secretion

• Consequences of impaired VLDL export on hepatic lipid accumulation

• Links between hepatocellular lipotoxicity, mitochondrial dysfunction, and oxidative stress

• Inflammatory and fibrogenic responses driving disease progression

Peer-reviewed studies from human clinical research, animal models, and mechanistic in vitro systems were prioritized. Evidence was evaluated for biological plausibility, consistency, and relevance to regulatory toxicology, with particular attention to chronic and low-dose perturbations relevant to EDC exposure.

This AOP is supported by strong biological plausibility and a growing body of empirical evidence linking impaired hepatic lipid export to MASLD progression. The sequence of key events reflects conserved metabolic and stress-response pathways observed across mammalian species and aligns with known clinical features of fatty liver disease associated with defects in lipoprotein secretion.

The AOP is well suited for screening, prioritization, and mode-of-action analysis of chemicals that interfere with GR signaling and hepatic lipid handling. While quantitative data are available for several individual relationships, uncertainties remain regarding threshold behavior and compensatory mechanisms, supporting its application primarily in hazard identification and integrated assessment frameworks.

Potential regulatory applications include:

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

• Support for integrated testing strategies targeting lipid handling and mitochondrial stress

• Grouping and read-across of chemicals affecting lipoprotein metabolism

• Informing assay development focused on VLDL secretion and hepatocellular lipid retention