Pre- and post-sexual maturity liver-specific ERa knockout does not impact hepatic mitochondrial function

Authors: FULLER, KELLY - University Of Kansas Medical School; ALLEN, JULIE - University Of Kansas Medical School; KUMARI, ROSHAN - University Of Kansas Medical School; AKAPO, JEPHTE - University Of Kansas Medical School; Ruebel, Meghan; SHANKAR, KARTIK - University Of Colorado; THYFAULT, JOHN - University Of Kansas Medical School

Submitted to: Journal of Endocrine Society
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/19/2023
Publication Date: 4/27/2023
Citation: Fuller, K.N., Allen, J., Kumari, R., Akapo, J.Y., Ruebel, M., Shankar, K., Thyfault, J.P. 2023. Pre- and post-sexual maturity liver-specific ERa knockout does not impact hepatic mitochondrial function. Journal of Endocrine Society. 7(6):bvad053. https://doi.org/10.1210/jendso/bvad053.
DOI: https://doi.org/10.1210/jendso/bvad053

Interpretive Summary: Compared to males, premenopausal women and female rodents are protected against increased fat accumulation in the liver and improved mitochondria. Recent evidence suggest that estrogen, which is produced at greater levels in females, may lead to this protective effect, although it is unclear how. ERa is a nuclear receptor that is largely involved in signaling in estrogen signaling to change metabolic effects. In this study, researchers found no differences in body weight/body fat or liver health in female mice with loss of ERa in the liver when given a high fat diet for either short-term (4 wk) or chronic (8 wk) duration. They also showed that in loss of ERa in the liver prior to puberty or at puberty did not alter liver mitochondrial function, but did lead to changes in liver gene expression and modest differences in bile acids. Together, these findings show that liver ERa is not required in female protection against fat accumulation in the liver or dysfunction of mitochondria in the liver.

Technical Abstract: Compared to males, premenopausal women and female rodents are protected against hepatic steatosis and present with higher functioning mitochondria (greater hepatic mitochondrial respiration and reduced H2O2 emission). Despite evidence that estrogen action mediates female protection against steatosis, mechanisms remain unknown. Here we validated a mouse model with inducible reduction of liver ERa (LERKO) via AAV Cre. We phenotyped the liver health and mitochondrial function of LERKO mice (n=10-12 per group) on a short-term high-fat diet (HFD), and then tested if timing of LERKO induction at 2 timepoints (sexually immature: 4 wks old (n=11 per group) vs. sexually mature: 8-10 wks old (n=8 per group)) would impact HFD-induced outcomes. We opted for an inducible LERKO model due to known estrogen-mediated developmental programming, and report both receptor and tissue specificity with our model. Control mice were ERa fl/fl receiving AAV with GFP only. Results show that there were no differences in body weight/composition or hepatic steatosis in LERKO mice with either short-term (4 wk) or chronic (8 wk) high-fat feeding. Similarly, LERKO genotype nor timing of LERKO induction (pre vs post sexual maturity) did not alter hepatic mitochondrial O2 and H2O2 flux, coupling, or OXPHOS protein. Transcriptomic analysis showed that hepatic gene expression in LERKO was significantly influenced by developmental stage. Together, these studies suggest that hepatic ERa is not required in female protection against HFD-induced hepatic steatosis nor does it mediate sexual dimorphism in liver mitochondria function.