Fatty liver linked to survival in E. coli infection

Scientists at UC San Francisco (UCSF) have developed a new way of looking at sex-biased diseases that has its roots in evolutionary biology.

They theorize that men and women took opposite paths in a balance between immunity and metabolism that occurs in the liver. This helped males fight off bacterial infections from wounds received in dominance fights, while helping females store subcutaneous fat to survive when food was scarce.

Working in mice, the scientists delineated 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 pose risks in today’s high-calorie environment. The findings have particular relevance to fatty liver, which affects a quarter of the US population. It is predominantly seen in men until women reach menopause.

“Recently, scientists have 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-senior author of the study, which appears Oct. 21, 2022 in Sciences. “Understanding these differences will be the key to unlocking therapies for sex-related 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 females developed hyperlipidemia, a condition also seen in humans with severe sepsis. Lowering their lipid levels helped them survive.

The researchers then examined how males and females respond to the contemporary environmental challenge of overeating by feeding mice high-fat food. The men developed fatty liver and glucose intolerance, which can lead to type 2 diabetes, but the women did not. This was true even when males and females gained a similar amount of weight.

Searching the literature for something that might explain this, the team 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 males and, along with it, their ability to survive infection.

“Host defense programs in the liver are the predisposing factors driving fatty liver in men,” said Joni Nikkanen, PhD, a postdoctoral fellow in the Department of Cellular Molecular Pharmacology, who began the work with co-senior author Ajay Chawla. , PhD, formerly at UCSF and now at Merck Research Labs.

“We have an evolutionary perspective on why such programs have been developed, because they protect men against bacterial infections,” he said. “But in another context, these same programs are no longer good for you, and you will develop more severe fatty liver.”

The team also examined how the presence of BCL6 affected gene expression in the liver. This process begins at puberty when men produce more testosterone and their pituitary glands begin to secrete growth hormone in sharp peaks and valleys.

These intermittent bursts, probably regulated by testosterone, are important. When the researchers infused male mice continuously with growth hormone the way it’s secreted in females, BCL6 disappeared from their livers and they lost the 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 pituitaries do not produce enough growth hormone. Boys are especially prone to fatty liver, but it goes away when they are given growth hormone to treat their short stature.

The work also broadens the scientific view of how the body fights infection to include organs such as the liver.

“The fight is still between infection and the immune system,” said Omer Gokcumen, PhD, an evolutionary anthropologist at the University at Buffalo and a co-author of the study. “But the liver is determining the battlefield.”

Other UCSF authors include Yew Ann Leong, William C. Krause, and Ethan J. Weiss. Please refer to the document for funding sources.

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