Hepatocyte ERα Mediates Estrogen-induced Augmentation of Hepatic Mitochondrial Respiration Following Ovariectomy

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ID: 325309
2026
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Abstract
Liver-specific ERα knockout (LERKO) mice with normal ovarian function are not susceptible to steatosis and maintain mitochondrial function. Here, we tested whether loss of hepatic ERα blunts estrogen modulation of hepatic mitochondrial respiratory capacity and mitochondrial proteome following ovariectomy (OVX). Sham or OVX surgery was performed in middle-aged female mice (36-40 weeks), followed by AAV injection to generate Control (Con; GFP) or LERKO mice (Cre). All mice were placed on a high-fat diet (HFD) for 10 weeks following surgery. Half of the OVX mice received 17-beta estradiol (E2) replacement (OVX + E2) for the last 4 weeks. OVX mice had greater body mass and adiposity, which was reversed by E2 replacement in both Con and LERKO mice. E2 replacement reduced steatosis in both Con and LERKO OVX mice, but the LERKO OVX mice maintained greater hepatic triglycerides. E2 replacement promoted greater basal and ADP-stimulated (State 3) mitochondrial respiration in Con OVX but not in LERKO OVX mice. Changes in mitochondrial respiration could not be attributed to altered responses to changes in energy demand (GATP) or to alterations in mitochondrial H2O2 production. Conversely, maximal coupled branched-chain amino acid-supported respiration was universally suppressed by E2 replacement. Proteomics analysis revealed E2-mediated reductions in hepatic mitochondrial energy transduction in both Con and LERKO mice. In conclusion, post-ovariectomy estrogen treatment reduces steatosis in the absence of hepatic ERα; however, steatosis remains higher, and mitochondrial deficits persist despite similar proteomic changes, suggesting ERα is required for optimal response to estrogen in modulating hepatic mitochondrial respiration.
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openalex_W7203697050 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Edziu Franczak, Benjamin A. Kugler, Sebastian F. Salathe, Julie Allen, Colin S. McCoin, E. Matthew Morris, John P. Thyfault
Journal american journal of physiology endocrinology and metabolism
Year 2026
DOI
10.1210/endocr/bqag093
URL
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