A fresh perspective on sex-biased diseases has been established by researchers at UC San Francisco (UCSF) that is based on evolutionary biology.
They hypothesize that males and females adopted opposing routes in the liver’s balance between immunity and metabolism. This helped men battle bacterial infections from dominance-fight wounds, while females stored subcutaneous fat to survive when food was short.
Working with mice, the researchers specify the activity of a signaling network that regulates lipids, with men accumulating fat in the liver and females releasing it into the bloodstream. Additionally, this system responds to growth hormones.
This phenomenon may have influenced male biology in ways that pose risks in the current high-calorie society. The findings are especially pertinent to fatty liver, which affects one-fourth of Americans. It is more common in men until women reach menopause.
Co-author Holly Ingram says that “scientists have only recently started to understand there are these profound differences between males and females.
“Understanding these differences,” according to the author, is going to be the key to unlocking therapeutics for sex-biased diseases. Fatty liver is one example.”
Experiments showed that male mice had a threefold greater chance of survival after being infected with E. coli than female mice. The females got a condition called hyperlipidemia, which can also happen to people with severe sepsis. To survive, they had to lower their lipid levels.
The researchers then fed the mice high-fat food to see how males and females deal with the modern environmental problem of overeating. Males, but not females, acquired fatty liver and glucose intolerance, which can result in Type 2 diabetes. This was true even when weight increase was similar for men and women.
The team looked through the scientific papers to explain this. They found something called BCL6 that stops the liver from breaking down fat and is much more common in male mice.
When the gene for this protein was taken out, the males lost their liver fat and, with it, their ability to fight off the infection.
“The host defense programs in the liver are the predisposing factors that drive fatty liver in males,” adds Joni Nikkanen, PhD, a postdoctoral fellow in the Department of Cellular Molecular Pharmacology.
“We have an evolutionary perspective on why such programs have developed—because they protect males against bacterial infections.
“But in another context, these same programs are not good for you anymore, and you will develop more severe fatty liver.”
The team also investigated how the presence of BCL6 influenced hepatic gene expression. This process begins when boys reach puberty and their pituitary glands begin to generate growth hormones in dramatic peaks and valleys.
These short bursts, which are probably controlled by testosterone, are very important. Growth hormone was continually pumped into male mice in the same way that it is secreted in females, but BCL6 vanished from their livers and they lost the ability to resist E. coli infection.
The findings suggest that growth hormone, an approach that is now being explored, may be used as a therapy for individuals with fatty liver disease. Its effects on kids whose pituitaries don’t produce enough growth hormone are already well-established. When administered growth hormones to correct their low stature, male children in particular stop developing fatty livers.
The research also broadens the scientific understanding of the body’s immune system to encompass organs like the liver.
“The fight is still between the infection and the immune system,” adds co-author Omer Gokcumen.
“But the liver is determining the battlefield.”
Image Credit: Getty
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