Estradiol treatment or modest exercise improves hepatic health and mitochondrial outcomes in female mice following ovariectomy

Abstract

We recently reported that compared to males, female mice have increased hepatic mitochondrial respiratory capacity and are protected against high-fat diet-induced steatosis. Here we sought to determine the role of estrogen in hepatic mitochondrial function, steatosis, and bile acid metabolism in female mice, as well as investigate potential benefits of exercise in the absence or presence of estrogen via ovariectomy (OVX). Female C57BL mice (n=6 per group) were randomly assigned to sham surgery (Sham), ovariectomy (OVX), or OVX plus estradiol replacement therapy (OVX+Est). Half of the mice in each treatment group were sedentary (SED) or had access to voluntary wheel running (VWR). All mice were fed a high-fat diet (HFD) and were housed at thermoneutral temperatures. We assessed isolated hepatic mitochondrial respiratory capacity using the Oroboros O2k with both pyruvate and palmitoylcarnitine as substrates. As expected, OVX mice presented with greater hepatic steatosis, weight gain, and fat mass gain compared to Sham and OVX+Est animals. Hepatic mitochondrial coupling (Basal/State 3 respiration) with pyruvate was impaired following OVX, but both VWR and estradiol treatment rescued coupling to levels greater than or equal to Sham animals. Estradiol and exercise also had different effects on liver electron transport chain protein expression depending on OVX status. Markers of bile acid metabolism and excretion were also impaired by ovariectomy but rescued with estradiol add-back. Together our data suggest that estrogen depletion impairs hepatic mitochondrial function and liver health, and that estradiol replacement and modest exercise can aid in rescuing this phenotype.

The Hepatoprotective and Hepatotoxic Roles of Sex and Sex-Related Hormones

“…Estrogen has a wide range of protective effects on hepatocytes. Estradiol reduces hepatic susceptibility to steatosis by strengthening cellular mitochondrial function in a substrate-specific manner ( 53 ). Moreover, 17β-estradiol (E 2 ) enhances hepatocytes mitochondrial content and oxidative capacity to alleviate hepatic lipid accumulation and oxidative stress.…”

Beyond the X Factor: Relevance of Sex Hormones in NAFLD Pathophysiology

“…Endurance training has been reported to be effective in reducing intra-hepatic lipid content and inflammation in post-menopausal women and OVX rodents [ 404 , 405 , 406 ]. Like estrogens, modest exercise improves hepatic health and mitochondrial outcomes in OVX females, by decreasing several genes of lipogenesis (e.g., Srebp-1c ; Chrebp , carbohydrate-responsive element-binding protein; Scd1 ; Acaca ) and several biomarkers of subclinical inflammation (e.g., Nf-kb, Tnfα , Il-6 ,) [ 407 ]. However, endurance exercise training prevents liver fat accumulation when exercise started after and not before OVX [ 408 ], suggesting that exercise must be conducted concurrently as estrogens withdrawal to be effective.…”

Early life stress exposure increases susceptibility to high fat/high sucrose diet in female mice

“…Obesity and diabetes have also been determined to increase the risk of developing nonalcoholic fatty liver disease. Of note, our group and others have repeatedly shown that females are protected from hepatic steatosis, a protection that goes away with experimental or natural loss of ovarian function (85, 86). Glucocorticoids have also been documented to stimulate free fatty acid release from adipose tissue resulting in increased ectopic lipid deposition in the liver (87, 88).…”