Monday, May 23, 2022

Good cholesterol may prevent liver inflammation

A study in mice, human blood samples, suggests HDL from the intestine may prevent liver inflammation.

High-density lipoprotein (HDL), produced by the liver and intestine, plays a significant role in cholesterol metabolism. It also has anti-inflammatory and antimicrobial properties.

The liver synthesizes HDL levels in the body. However, the role of HDL produced by the intestine differs from the HDL produced by the liver, has not been identified.

A new study has identified the previously unknown role of good cholesterol. The study by the scientists from Washington University School of Medicine in St. Louis identified the role of a particular type of HDL called HDL3 (good cholesterol), produced by the intestine. They found that good cholesterol levels prevent liver inflammation by blocking gut bacterial signals that cause liver inflammation.

Senior author Gwendalyn J. Randolph, Ph.D., the Emil R. Unanue Distinguished Professor of Immunology, 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.”

Some premature infants develop a life-threatening condition called necrotizing enterocolitis. Necrotizing enterocolitis (NEC) is a serious gastrointestinal problem that needs a portion of the intestine to be surgically removed. Even after successful bowel surgery, such babies often develop liver disease.

To understand why this happens, scientists studied the problem in a mouse model with the same 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 cholesterol might interfere with lipopolysaccharide detection by immune cells. The receptor for lipopolysaccharide might be linked to liver disease following bowel surgery.

Randolph said, “However, no one thought that HDL would directly move from the intestine to the liver, which requires that it enter the portal vein. 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 a light on different organs and track the HDL from that organ. So, we wanted to shine a 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.”

While on its route to the portal vein, HDL3 binds to a protein called LBP — lipopolysaccharide-binding protein. The protein binds to the harmful lipopolysaccharide, blocking it from activating immune cells called Kupffer cells. These Kupffer cells are macrophages in the liver, when activated by lipopolysaccharide, can drive liver inflammation.

When LBP is part of the HDL3 complex, it prevents the harmful bacterial molecule from activating the liver Kupffer cells and inducing inflammation.

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

It was found that reduced HDL cholesterol levels can worsen liver injury.

Randolph said“The surgery seems to cause two problems. A shorter intestine means making less HDL3, and the surgery itself leads to an injurious state in the gut, allowing 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, HDL3 was protective, binding to the additional lipopolysaccharide released from the injured intestine and blocking its downstream inflammatory effects in the liver.”

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

Journal Reference:
  1. Yong-Hyun Han et al. Enterically derived high-density lipoprotein restrains liver injury through the portal vein. DOI: 10.1126/science.abe6729

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