Pre- and Post-Sexual Maturity Liver-specific ERα Knockout Does Not Impact Hepatic Mitochondrial Function

Area of Science:

• Endocrinology
• Hepatology
• Mitochondrial Biology

Background:

• Premenopausal women and female rodents exhibit protection against hepatic steatosis compared to males.
• Estrogen action is implicated in this protective mechanism, but the specific pathways remain largely unknown.
• Liver estrogen receptor alpha (ERα) is a key mediator of estrogen signaling in the liver.

Purpose of the Study:

• To investigate the role of liver ERα in protection against high-fat diet (HFD)-induced hepatic steatosis in female mice.
• To determine if ERα mediates sexual dimorphism in hepatic mitochondrial function.
• To assess the impact of developmental timing of ERα reduction on HFD outcomes.

Main Methods:

• Validation of an inducible mouse model with liver-specific reduction of ERα (LERKO) using adeno-associated virus (AAV) Cre.
• Phenotyping liver health and mitochondrial function (respiration, H2O2 emission, OXPHOS proteins) in LERKO mice fed a HFD.
• Comparison of outcomes based on timing of LERKO induction (pre- vs. post-sexual maturity).

Main Results:

• No significant differences in body weight, body composition, or hepatic steatosis were observed between LERKO and control mice on HFD.
• Hepatic mitochondrial oxygen consumption, hydrogen peroxide emission, coupling, and OXPHOS protein levels were not altered by LERKO genotype or induction timing.
• Transcriptomic analysis revealed that developmental stage significantly influenced hepatic gene expression in LERKO mice.

Conclusions:

• Hepatic ERα is not required for the protection against HFD-induced hepatic steatosis observed in female mice.
• ERα does not appear to mediate the sexual dimorphism in hepatic mitochondrial function.
• Developmental timing influences hepatic gene expression, but ERα's role in HFD response is minimal in females.