Study Suggests “Good Cholesterol” May Protect Liver, Health News, ET HealthWorld


Washington: A new study by researchers at Washington University School of Medicine in St. Louis suggests that a 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 was published in the journal Science.

HDL is best known to absorb cholesterol from the body and deliver it to the liver for elimination. But in the new study, researchers have identified a special type of HDL called HDL3 which, when produced by the gut, blocks intestinal bacterial signals that cause inflammation in the liver.

If left unblocked, these bacterial signals travel from the intestine to the liver, where they activate immune cells that trigger an inflammatory condition, resulting in liver damage.

“Even though HDL has been considered ‘good cholesterol’, drugs that increase overall HDL levels have fallen out of favor in recent years due to clinical trials that have shown no benefit in cardiovascular disease,” said senior author Gwendalyn J. Randolph, PhD, the Emil R. Unanue Emeritus Professor of Immunology.

Randolph added: “But our study suggests that increasing the levels of this specific type of HDL, and particularly the increase in the gut, may hold promise for protection against liver disease, which, like disease heart problems, are also a major chronic health problem. ” In the study, the researchers showed that HDL3 from the gut protects the liver from inflammation in mice.

Any type of intestinal damage can impact how a group of microbes called Gram-negative bacteria can affect the body. These microbes produce an inflammatory molecule called lipopolysaccharide which can travel to the liver via the portal vein. The portal vein is the main vessel that supplies blood to the liver, and it carries most of the nutrients to the liver after food is absorbed in the intestine.

Substances from gut microbes can travel with nutrients from food to activate immune cells that trigger inflammation. In this way, elements of the gut microbiome can lead to liver disease, including fatty liver disease and liver fibrosis, in which the liver develops scar tissue.

Randolph became interested in this topic through collaboration with two surgeons at the University of Washington, Emily J. Onufer, MD, surgical resident, and Brad W. Warner, MD, Jessie L. Ternberg PhD, MD, professor distinguished pediatric surgery and chief surgeon. at St. Louis Children’s Hospital, the two co-authors of the study.

Some premature infants develop a life-threatening condition called necrotizing enterocolitis, an inflammation of the intestine that may require surgical removal of part of the intestine. Even after successful bowel surgery, these babies often develop liver disease, and Onufer and Warner wanted to understand why.

“They were studying this problem in a mouse model of the disease: they remove part of the small intestine in mice and study the resulting liver fibrosis,” Randolph said. “There was evidence in the literature that HDL might interfere with detection of lipopolysaccharide by immune cells and that the lipopolysaccharide receptor might be linked to liver disease after bowel surgery.

“However, no one thought that HDL would pass directly from the intestine to the liver, which requires it to enter the portal vein,” she said. “In other tissues, HDL passes through another type of vessel called a lymphatic vessel which in the intestine does not connect to the liver. We have a very nice tool in our lab that allows us to shed light on different organs and track HDL from that organ. So we wanted to shed some light on the gut and see how HDL goes and where it goes from there. This is how we showed that HDL3 only comes out through the portal vein to go directly to the liver. “

As HDL3 makes this short journey through 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 prevented from activating immune cells called Kupffer cells. These are macrophages that reside in the liver and, when activated by a lipopolysaccharide, can lead to inflammation of the liver.

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 Kupffer cells in the liver and inducing inflammation, according to experiments conducted by first author Yong-Hyun Han, PhD, when he was postdoctoral researcher in Randolph’s lab. Han is now a faculty member at National Kangwon University in South Korea.

“We believe that LBP, only when bound to HDL3, physically hinders, so the lipopolysaccharide cannot activate inflammatory immune cells,” Han said. “HDL3 essentially hides the harmful molecule. However, if LBP binds to lipopolysaccharide and HDL3 is not present, LBP cannot block it. Without HDL3, LBP will trigger stronger inflammation.”

Researchers have shown that liver damage is worse when HDL3 in the intestine is reduced, for example during the surgical removal of part of the intestine.

“The operation appears to cause two problems,” Randolph said. “A shorter intestine means it produces less HDL3, and the surgery itself causes a detrimental condition in the intestine, allowing more lipopolysaccharides to leak into the bloodstream. When you remove the part of the intestine that produces the most HDL3, you get the worst results for the liver.

When you have a mouse that cannot genetically produce HDL3, the inflammation in the liver 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 damage, the researchers found that HDL3 was protective, binding to additional lipopolysaccharide released by the injured gut and blocking its inflammatory effects downstream in the liver.

The researchers further showed that the same protective molecular complexes were present in human blood samples, suggesting that a similar mechanism is present in humans. 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 damage. Although the drug is only available for animal research, the study reveals new possibilities for treating or preventing liver disease, whether it comes from damage to the intestine caused by high-fat diets, overconsumption. alcohol or physical injury, such as surgery.

“We hope 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.”

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