What is the clinical evidence from this study?

Study design: Other. Population: Metabolic dysfunction-associated steatotic liver disease (MASLD) (n=243). Intervention: 17β-estradiol (Estrogen) vs. Untreated/vehicle. Primary outcome: Reactive oxygen species (ROS) levels and lipid droplet accumulation.

January 31, 2025Cell Death and Disease22 citationsOpen Access

Estrogen-dependent activation of TRX2 reverses oxidative stress and metabolic dysfunction associated with steatotic disease

ASAlfredo SmirigliaUniversity of Florence NLNicla LoritoUniversity of Florence MBMarina BacciUniversity of Sassari

Key Result

Estrogen treatment reduced reactive oxygen species levels and lipid droplet content in steatotic-induced liver cells by upregulating the mitochondrial thioredoxin 2 (TRX2) antioxidant system.

Structured PICO

Does 17β-estradiol reduce oxidative stress and lipid accumulation in preclinical in vitro models of steatotic liver disease?

Population

Preclinical in vitro study utilizing human and murine liver cell lines, supported by an in silico transcriptomic analysis of 243 female liver tissue samples across various stages of MASLD.

Intervention

17β-Estradiol (E2) 1 nM or 50 nM for 48 hours

Comparator

Vehicle/no estrogen in steatotic-induced cells

Outcome

Reactive oxygen species (ROS) levels, lipid droplet (LD) content, and mitochondrial integritysurrogate

Estrogen protects against oxidative stress and lipid accumulation in in vitro models of steatotic liver disease via upregulation of the mitochondrial antioxidant TRX2.

Limitations

Blinding was not implemented during the experimental processes.
In vitro models may not fully recapitulate the complexity of human liver tissue and the role of stromal/immune cells.
Lack of in vivo experimental models to confirm the specific mechanisms underlying TRX2 and estrogen receptor interactions.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of hepatic disorders, ranging from simple steatosis to steatohepatitis, with the most severe outcomes including cirrhosis, liver failure, and hepatocellular carcinoma. Notably, MASLD prevalence is lower in premenopausal women than in men, suggesting a potential protective role of estrogens in mitigating disease onset and progression. In this study, we utilized preclinical in vitro models-immortalized cell lines and hepatocyte-like cells derived from human embryonic stem cells-exposed to clinically relevant steatotic-inducing agents. These exposures led to lipid droplet (LD) accumulation, increased reactive oxygen species (ROS) levels, and mitochondrial dysfunction, along with decreased expression of markers associated with hepatocyte functionality and differentiation. Estrogen treatment in steatotic-induced liver cells resulted in reduced ROS levels and LD content while preserving mitochondrial integrity, mediated by the upregulation of mitochondrial thioredoxin 2 (TRX2), an antioxidant system regulated by the estrogen receptor. Furthermore, disruption of TRX2, either pharmacologically using auranofin or through genetic interference, was sufficient to counteract the protective effects of estrogens, highlighting a potential mechanism through which estrogens may prevent or slow MASLD progression.

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