HDL from the intestine may prevent liver inflammation
Washington University School of Medicine
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."
