UC San Francisco (UCSF) researchers have developed a new way of looking at sex-biased diseases that is rooted in evolutionary biology.
They theorize that men and women have taken opposite paths in the trade-off between immunity and metabolism that occurs in the liver. This helped males fight off bacterial infections from wounds they sustained in the struggle for dominance, while also helping females store subcutaneous fat to survive when food was scarce.
Working in mice, the researchers pinpointed the activity of a signaling pathway that regulates lipids, storing fat in the liver in males and releasing it into the bloodstream in females. This pathway also responds to growth hormone.
This phenomenon may have shaped male biology in ways that carry risks in today’s high-calorie environment. The findings are of particular relevance to fatty liver disease, which affects a quarter of the US population. It occurs mostly in men until women reach menopause.
“Scientists have only recently begun to understand that there are these profound differences between men and women,” said Holly Ingraham, PhD, Herzstein Professor of Molecular Physiology at UCSF and co-author of the study, which appears Oct. 21, 2022. Science. “Understanding these differences will be key to unlocking therapeutics for sex-biased diseases. Fatty liver is one example.”
The experiments found that male mice were three times more likely than female mice to survive infection with the bacteria E-coli. The women developed hyperlipidemia, a condition that is also seen in people with severe sepsis. Lowering their lipid levels helped them survive.
The investigators then examined how males and females responded to the current environmental challenge of overeating by feeding the mice a high-fat diet. Men developed fatty liver and glucose intolerance, which can lead to type 2 diabetes, but not women. This was true even though males and females gained similar weight.
When the team searched the literature for an explanation, they identified a transcription factor called BCL6, which prevents the breakdown of fat in the liver and is much more present in male mice.
Deleting the gene for this protein eliminated liver fat in the men, and with it, their ability to survive infection.
“Host defense programs in the liver are predisposing factors that cause fatty liver in men,” said Joni Nikkanen, PhD, a postdoctoral fellow in the Department of Cellular Molecular Pharmacology who began the work with co-author Ajay Chawla, PhD. , formerly of UCSF and now at Merck Research Labs.
“We have an evolutionary view of why such programs evolved — because they protect men from bacterial infections,” he said. “But in a different context, those same programs are no longer good for you, and you develop more severe fatty liver disease.”
The team also investigated how the presence of BCL6 affected gene expression in the liver. This process begins at puberty, when men produce more testosterone and their pituitary gland begins to secrete growth hormone in sharp peaks and valleys.
These intermittent bursts, probably regulated by testosterone, are important. When researchers continuously infused male mice with growth hormone as it is secreted by females, BCL6 disappeared from their livers and they lost their ability to fight. E-coli infection.
The results point to growth hormone as a potential therapy for adults with fatty liver disease, an idea that is currently being tested. Its effects are already well established in children whose pituitary gland does not produce enough growth hormone. Male children in particular tend to develop fatty liver, but this disappears when they are given growth hormone to treat short stature.
The work also expands the scientific view of how the body fights infection to include organs such as the liver.
There is still a battle between the infection and the immune system. But the liver determines the battlefield.”
Omer Gokcumen, PhD, evolutionary anthropologist, University at Buffalo and co-author of the study
University of California – San Francisco
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