Washington University School of Medicine, July 26, 2021

The body’s so-called good cholesterol may be even better than we realize. New research from Washington University School of Medicine in St. Louis suggests that one type of high-density lipoprotein (HDL) has a previously unknown role in protecting the liver from injury. This HDL protects the liver by blocking inflammatory signals produced by common gut bacteria.

The study is published July 23 in the journal Science.

HDL is mostly known for mopping up cholesterol in the body and delivering it to the liver for disposal. But in the new study, the researchers identified a special type of HDL called HDL3 that, when produced by the intestine, blocks gut bacterial signals that cause liver inflammation. If not blocked, these bacterial signals travel from the intestine to the liver, where they activate immune cells that trigger an inflammatory state, which leads to liver damage.

“Even though HDL has been considered ‘good cholesterol,’ drugs that increase overall HDL levels have fallen out of favor in recent years because of clinical trials that showed no benefit in cardiovascular disease,” said senior author Gwendalyn J. Randolph, PhD, the Emil R. Unanue Distinguished Professor of Immunology. “But our study suggests that raising levels of this specific type of HDL, and specifically raising it in the intestine, may hold promise for protecting against liver disease, which, like heart disease, also is a major chronic health problem.” In the study, the researchers showed that HDL3 from the intestine protects the liver from inflammation in mice.

Any sort of intestinal damage can impact how a group of microbes called Gram-negative bacteria can affect the body. Such microbes produce an inflammatory molecule called lipopolysaccharide that can travel to the liver via the portal vein. The portal vein is the major vessel that supplies blood to the liver, and it carries most nutrients to the liver after food is absorbed in the intestine. Substances from gut microbes may travel along with nutrients from food to activate immune cells that trigger inflammation. In this way, elements of the gut microbiome may drive liver disease, including fatty liver disease and liver fibrosis, in which the liver develops scar tissue.

Randolph became interested in this topic through a collaboration with two Washington University surgeons, Emily J. Onufer, MD, a surgical resident, and Brad W. Warner, MD, the Jessie L. Ternberg PhD, MD, Distinguished Professor of Pediatric Surgery and chief surgeon at St. Louis Children’s Hospital, both co-authors on the study. Some premature infants develop a life-threatening condition called necrotizing enterocolitis, an inflammation of the intestine that can require a portion of the intestine to be surgically removed. Even after a successful bowel surgery, such babies often develop liver disease, and Onufer and Warner wanted to understand why.

“They were studying this problem in a mouse model of the condition: They remove a portion of the small intestine in mice and study the liver fibrosis that results,” Randolph said. “There were hints in the literature that HDL might interfere with lipopolysaccharide’s detection by immune cells and that the receptor for lipopolysaccharide might be linked to liver disease following the bowel surgery.

“However, no one thought that HDL would directly move from the intestine to the liver, which requires that it enter the portal vein,” she said. “In other tissues, HDL travels out through a different type of vessel called a lymphatic vessel that, in the intestine, does not link up to the liver. We have a very nice tool in our lab that lets us shine light on different organs and track the HDL from that organ. So, we wanted to shine light on the intestine and see how the HDL leaves and where it goes from there. That’s how we showed that HDL3 leaves only through the portal vein to go directly to the liver.”

As the HDL3 makes this short journey down the portal vein, it binds to a protein called LBP — lipopolysaccharide binding protein — which binds to the harmful lipopolysaccharide. When the harmful lipopolysaccharide is bound to this complex, it is blocked from activating immune cells called Kupffer cells. These are macrophages that reside in the liver and, when activated by lipopolysaccharide, can drive liver inflammation.

As a complex of proteins and fats, HDL3 uses its partnership with LBP to bind to lipopolysaccharide. When LBP is part of the HDL3 complex, it prevents the harmful bacterial molecule from activating the liver Kupffer cells and inducing inflammation, according to experiments conducted by first author Yong-Hyun Han, PhD, when he was a postdoctoral researcher in Randolph’s lab. Han is now on the faculty of Kangwon National University in South Korea.

“We think that LBP, only when bound to HDL3, is physically standing in the way, so lipopolysaccharide can’t activate the inflammatory immune cells,” Han said. “HDL3 is essentially hiding the harmful molecule. However, if LBP is binding to lipopolysaccharide and HDL3 is not present, LBP is not able to stand in the way. Without HDL3, LBP is going to trigger stronger inflammation.”

The researchers showed that liver injury is worse when HDL3 from the intestine is reduced, such as from surgical removal of a portion of the intestine.

“The surgery seems to cause two problems,” Randolph said. “A shorter intestine means it’s making less HDL3, and the surgery itself leads to an injurious state in the gut, which allows more lipopolysaccharide to spill over into the portal blood. When you remove the part of the intestine that makes the most HDL3, you get the worst liver outcome. When you have a mouse that cannot genetically make HDL3, liver inflammation is also worse. We also wanted to see if this dynamic was present in other forms of intestinal injury, so we looked at mouse models of a high-fat diet and alcoholic liver disease.”

In all of these models of intestinal injury, the researchers found that HDL3 was protective, binding to the additional lipopolysaccharide released from the injured intestine and blocking its downstream inflammatory effects in the liver.

The researchers further showed that the same protective molecular complexes were present in human blood samples, suggesting a similar mechanism is present in people. They also used a drug compound to increase HDL3 in the intestines of mice and found it to be protective against different types of liver injury. While the drug is only available for animal research, the study reveals new possibilities for treating or preventing liver disease, whether it stems from damage to the intestine caused by high-fat diets, alcohol overuse or physical injury, such as from surgery.

“We are hopeful that HDL3 can serve as a target in future therapies for liver disease,” Randolph said. “We are continuing our research to better understand the details of this unique process.”

Colorado State University, July 26, 2021

Neuroscientists have long known that aerobic exercises, like walking, swimming, running, or biking, are largely beneficial for brain health. Now, new research out of Assistant Professor Aga Burzynska’s BRAiN Lab at Colorado State University provides some of the first evidence that white matter, which connects and carries signals between neurons, can also change for the better in response to aerobic exercise, giving a boost to participants’ memory recall.

The study, published in NeuroImage on June 24, found that regions of the brain most vulnerable to aging were also the regions that benefitted most from aerobic exercise, suggesting that regular aerobic exercise is an effective strategy to reduce the risk of cognitive decline in a world where the incidence of dementia is expected to double every 20 years as the population ages.

White matter vs. gray matter

White matter is commonly regarded as a passive brain tissue that takes a backseat to its active, gray matter counterpart, where powerful neurons live. If neurons are the brain cells that generate signals and electrical impulses, then axons in white matter are the wiring that transmit those signals between neurons.

White matter is mostly made up of the brain’s axon wiring; it received its “white” namesake due to the fatty proteins and lipids that coat the axon fibers. The insulation provided by those proteins and lipids helps to increase the speed at which signals can be passed from one brain region to another.

While neurodegeneration is often associated with a loss of neurons with age, and therefore a loss of gray matter, aging white matter can also impair cognitive health. A reduction in axon fibers, as well as lesions and microbleeds, are associated with age-related deficits in brain function; thus, interventions to prevent white matter aging are also important to the prevention of Alzheimer’s disease and other dementias.

A test of exercise

In Burzynska’s latest study, her team gathered a sample of 180 older adults who were healthy, but admittedly inactive—the ideal population to study when developing a baseline of how effective exercise can be.

“We decided to include healthy participants so that we can first understand what’s ‘more normal’ in healthy aging and further apply this knowledge later on in other populations, such as people with dementia,” said Andrea Mendez Colmenares, Burzynska’s graduate student and first author on the study.

Participants were then randomly separated into groups that met three times per week over the course of six months. One group walked for about 40 minutes at each session. Another group took a dance class that got progressively harder over the course of six months. And the final group, which acted as a control for the study, was limited to balance and stretch exercises that purposely aimed to keep their heart rates low.

Each participant underwent a series of magnetic resonance imaging and cognitive and cardiorespiratory testing before and after the intervention to assess the effects of physical activity on the brain.

Cutting-edge techniques

To gauge the change in white matter over time, the team employed a technique called the T1w/T2w ratio, which involved MRI scans of the participants’ brains.

When MRI scans are taken, most often researchers and doctors are looking at T1-weighted and T2-weighted images. These are the black, white, and gray images of the brain often seen on TV medical dramas when the character’s brain is injured. In a T1-weighted image, white matter of the brain appears white, and gray matterappears gray, but on a T2-weighted image, the colors are inverted. It’s the coloring that helps researchers identify changes in brain anatomy, such as tumors, atrophy, or in this case, changes in white matter.

Since T1-w and T2-w images are widely available in most research studies, the team decided to combine the images to create a ratio to enhance the contrast that refers to the white matter of the brain. Using algorithms and advanced statistics, the team was able to extract values that show how specific regions of white matter changed over the course of the six-month intervention.

Mendez Colmenares also employed other white matter metrics using the more common technique of diffusion weighted imaging and by studying brain volume and lesions on the brain. Together, the metrics used led to one of the most comprehensive studies of white matter to date.

Increased white matter

Using the T1w/T2w ratio technique, the team found that participants in the walking and dance groups had an increase in their white matter after six months of aerobic exercise.

In other words, physical activity positively affected the brain’s white matter, but especially in regions most vulnerable to aging, such as the corpus callosum and cingulum, which confer important cognitive abilities, such as memory and executive function.

Further, the walking group experienced the added benefit of improved episodic memory after the intervention and were more able to recall memories from their lifetimes.

“This might be because the walking group had more people versus the dancing group, but we have strong reasons to believe this may be because the walking group had a stronger aerobic component, like they and their hearts were working harder,” Mendez Colmenares said.

Thus, activities that really raise the heart rate might be better equipped to combat certain side effects of brain aging.

However, the opposite is true of activities that aren’t as vigorous: Participants in the team’s study who were limited to low-intensity exercises, such as stretching or balancing postures, experienced a normal, slow decline in white matter signal over six months, and no changes in episodic memory.

A little goes a long way

Taken together, the results support public health recommendations for regular moderate-to-vigorous physical activity, specifically 150 minutes of physical activity per week, according to the American Heart Association and other health organizations.

Further, the findings strengthen the idea that white matter is “plastic” and able to change as a result of experience or intervention, even in the short-term—some positive news for those who might be looking to add more exercise to their lifestyles.

“The fact that we were able to show results in white matter in a clinical trial in only six months means that you don’t need to exercise your entire life to show some changes in your brain,” Mendez Colmenares said.

Mendez Colmenares added that she hopes this research paves the way for personalized recommendations in the future that tailor exercise to what works best for each individual, based on their own biology and physiology.

“We hope this can advance the field of white matter aging and dementia in the way that more recommendations for non-pharmacological treatments and lifestyle interventions can be better directed to people who are aging normally, and to people who have some impairment, so that people can live independently for longer and with better cognition,” she said.

Moving forward, Burzynska’s BRAiN Lab is drilling down into other, more advanced white matter techniques to help verify the findings and better understand the mechanisms controlling white matter alterations in the brain.

And, as is the way of science, it’s now up to other researchers to test the team’s findings and see if they can replicate similar results.