URBANA, Ill. – Postmenopausal women have an increased risk of non-alcoholic fatty liver disease due to the loss of estrogen due to metabolic changes. A high-fat diet further exacerbates the disease, which can lead to cirrhosis and failure of the liver. Hormone replacement therapy (HRT) is an effective treatment, but it has an increased risk of breast cancer, uterine cancer, and cardiovascular disease.
A research team from the University of Illinois has identified a new estrogen compound, the pathway-preferential estrogens, which provide benefits similar to HRT, but without risk factors. In previous research, the team showed that the compound activates specific signaling pathways, particularly in metabolic tissue.
In a new article published in Nutrients, researchers investigate the effects of signaling-pathway estrogens on liver and uterus health in mice.
“Estrogens are important for the reproductive system and metabolic tissue. Hormone replacement therapy can solve some of the metabolic problems associated with the onset of menopause. But we know that it also increases the risks associated with exposure to the hormones, ”says Zeynep Madak-Erdogan, associate professor in the Department of Food Science and Human Nutrition at U of I and lead author of the new study.
“We removed the ovaries from the mice to mimic the loss of estrogen that occurs in menopausal women. We also put the mice on a high fat diet and they gained weight pretty quickly. We treated one group of mice with hormone replacement therapy and another group of mice with estrogens, which prefer the metabolic pathway, ”explains Madak-Erdogan.
The researchers observed the mice for six weeks and measured their food intake and body composition. At the end of the experiment, they collected liver and uterine tissues for analysis.
“Normally, estrogen leads to an increase in uterine weight, but this was not the case with the preferred route estrogens. That is a good thing because it indicates that there are no negative effects on the uterus, ”says Madak-Erdogan.
Treatment with estrogens, or estrogens with preferential pathways, can help reduce excessive lipid deposition in the liver. So much is already known, says Madak-Erdogan.
“The new thing about this work is that we used genomic sequencing. Specifically, we looked at the changes in liver cells from the addition of estrogens with preferential metabolism and how it compares to what happens when you give estrogen, ”she notes.
“We found that the formation of new mitochondria with oestrogens with a preferential signaling pathway increased. Mitochondria are a powerhouse, and you need healthy new mitochondria to keep your cells functioning. This is particularly important for the liver cells, the hepatocytes. “
As a result, although the mice received more calories, they also burned more when given metabolically preferential estrogens. The compound can also prevent fibrosis from progressing.
“As non-alcoholic fatty liver disease progresses from lipid deposition to cirrhosis, it further damages liver cells and fibrosis begins. If you accumulate more lipids, this causes oxidative stress and begins to damage the hepatocytes, ”explains Madak-Erdogan.
“When we treated the animals with estrogens, which prefer the metabolic pathway, the reduction in fibrosis compared to estrogen was much greater. The compound causes a higher utilization of the food intake, but also protects against damage from the excess food itself and from lipid deposits. This means that estrogens, which prefer the pathway, prevent further fibrosis, which is the pathway that leads to liver failure and metabolic problems. “
Pathway-preferential estrogens are structurally estrogens that act by ingesting estrogen receptors, but because of the compound’s unique properties, they improve liver health without further harming reproductive tissues, the researchers note.
John Katzenellenbogen, research professor of chemistry at U of I, developed the preferred estrogen pathway in his research laboratory. The drug is still in preclinical testing and researchers continue to monitor its effects on body tissues in animal studies.
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