HDL3 Protects Against Liver Inflammation

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A new study from Washington University School of Medicine in St. Louis has indicated that a type of “good cholesterol” coined HDL3, when produced in the intestine, protects the liver from inflammation and injury.

The study published on July 23, 2021, in the journal Science, suggested that a type of high-density lipoprotein known as HDL has in the past protected the liver from injury by blocking inflammatory signals that are produced by the gut bacteria.

A special type of HDL called the HDL3 was identified as an offshoot of the previously known HDL famed for mopping up cholesterol in the body and transporting it to the liver for onward disposal. Bacterial signals move from the intestine to the liver, and then activate immune cells that trigger inflammation leading to liver damage. The HDL3, when produced in the intestine would block gut bacterial signals responsible for inflammation.

Senior author of the study and the Emil R. Unanue Distinguished Professor of Immunology, Mr. Gwendalyn J. Randolph, PhD said:

“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. 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.”

The researchers in the study showed that HDL3 from the intestine protects the liver from inflammation in mice.

A damage to the intestine can have an effect onhow a group of microbes called Gram-negative bacteria can affect the body, with the microbesproducing an inflammatory molecule called lipopolysaccharide that travels to the liver via the portal vein. The portal vein, a major vessel that supplies blood to the liver, carries most nutrients to the liver after food is absorbed in the intestine. In the process, substances from gut microbes may be transported along with nutrients from food to activate immune cells that trigger inflammation. This may cause elements of the gut microbiome todrive liver disease, including fatty liver disease and liver fibrosis, in which the liver develops scar tissue.

Randolph in 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-authorson the study looked at how 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.

According to Randolph:

“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. 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.”

Down the portal vein, the HDL3 binds to a protein called LBP — lipopolysaccharide binding protein and when the harmful lipopolysaccharide is bound to this complex, it is disallowed from activating immune cells known as Kupffer cells. The macrophages that reside in the liver when activated by lipopolysaccharide, causes liver inflammation.

“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 further proved that liver injury is worse when HDL3 from the intestine is reduced, from the surgical removal of a portion of the intestine.

“The surgery seems to cause two problems. 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.” ,” Randolph said.

The researchers found that HDL3 was protective, binding to the additional lipopolysaccharidereleased 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.”

Reference: “Enterically derived high-density lipoprotein restrains liver injury through the portal vein” by Yong-Hyun Han, Emily J. Onufer, Li-Hao Huang, Robert W. Sprung, W. Sean Davidson, Rafael S. Czepielewski, Mary Wohltmann, Mary G. Sorci-Thomas, Brad W. Warner and Gwendalyn J. Randolph, 23 July 2021, Science.
DOI: 10.1126/science.abe6729