Studies in mouse and human blood samples suggest that HDL from the intestine may prevent liver inflammation-ScienceDaily

This study was published in the journal on July 23 Science..

HDL is primarily known for wiping off cholesterol in the body and transporting it to the liver for disposal. However, in a new study, researchers have identified a special type of HDL called HDL3. It blocks the signal of gut microbiota, which, when produced in the intestine, causes inflammation of the liver. When unblocked, these bacterial signals travel from the intestine to the liver, where they activate immune cells, causing an inflammatory condition and causing liver damage.

“HDL has been considered’good cholesterol’, but clinical trials have shown that it has no effect on cardiovascular disease, so drugs that raise overall HDL levels have become less popular in recent years.” Senior author Dr. Gwendarin J. Randolph said. Emil R. Unanue A prominent professor of immunology. “But our study shows that raising levels of this particular type of HDL, especially in the intestines, is promising for protection from liver disease, which is a major chronic health problem as well as heart disease. In this study, researchers showed that HDL3 from the intestine protects the liver from inflammation in mice.

Intestinal damage of all kinds can affect how a group of microorganisms called Gram-negative bacteria affect the body. These microorganisms produce an inflammatory molecule called lipopolysaccharide that can move to the liver via the portal vein. The portal vein is the main blood vessel that supplies blood to the liver and carries most of the nutrients to the liver after food is absorbed by the intestines. Substances from gut microbiota can move with nutrients from food and activate immune cells that cause inflammation. Thus, components of the gut microbiota can cause liver disease such as fatty liver disease and liver fibrosis, and the liver develops scar tissue.

Randolph became interested in this topic through a collaboration between two surgeons at the University of Washington, Dr. Emily J. Onufer, a surgeon, and Dr. Brad W. Warner, MD, a prominent professor and chief of pediatric surgery. .. Surgeon at St. Louis Children’s Hospital, both co-authors of the study. Some premature babies develop a life-threatening condition called necrotizing enterocolitis. Necrotizing enterocolitis is an inflammation of the intestine that requires surgical removal of part of the intestine. Even after 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 this condition. They are studying the resulting cirrhosis by removing part of the mouse’s small intestine,” Randolph said. “There was a hint in the literature that HDL could interfere with the detection of lipopolysaccharide by immune cells, and that lipopolysaccharide receptors may be associated with liver disease after bowel surgery.

“But no one thought that HDL would move directly from the gut to the liver, so we need to enter the portal vein,” she said. “In other tissues, HDL exits through another type of blood vessel called the lymph vessels, but in the intestines it does not connect to the liver. Our laboratory sheds light on various organs. There is a very good tool that can track HDL from that organ, so I wanted to shed light on the intestines to see how HDL came out and where it went from there. Thus, we have shown that HDL3 exits only from the portal vein and goes directly to the liver. “

When HDL3 makes this short journey down the portal vein, it binds to a protein called LBP (a lipopolysaccharide binding protein). It binds to the harmful lipopolysaccharide. The binding of harmful lipopolysaccharides to this complex blocks the activation of immune cells called Kupffer cells. These are macrophages present in the liver that, when activated by lipopolysaccharide, can cause liver inflammation.

As a protein-fat complex, HDL3 uses a partnership with LBP to bind lipopolysaccharide. When LBP is part of the HDL3 complex, harmful bacterial molecules activate Kupffer cells in the liver, according to an experiment conducted by lead author Dr. Yong Hyun Han when he was a postdoctoral fellow in Randolph’s lab. Prevents it from becoming and inducing inflammation. Han is currently enrolled in a faculty at Gangwon-do University in South Korea.

“Lipopolysaccharides cannot activate inflammatory immune cells because we believe that LBP is physically disturbing only when it binds to HDL3,” Han said. “HDL3 hides harmful molecules in nature. However, if LBP is bound to lipopolysaccharide and HDL3 is absent, LBP does not get in the way. Without HDL3, LBP causes more intense inflammation. Cause. “

Researchers have shown that a decrease in HDL3 from the intestine, such as surgical removal of part of the intestine, exacerbates liver damage.

“Surgery seems to cause two problems,” Randolph said. “A short intestine means less HDL3 production, the surgery itself can lead to harmful conditions in the intestine, and more lipopolysaccharide can spill into the blood of the portal vein. HDL3 most Removing the high-producing part of the intestine also exacerbates liver inflammation when using mice that cannot genetically produce HDL3, and whether this dynamics is present in other forms of intestinal damage. I wanted to confirm, so I had a high-fat diet and alcoholic liver disease. “

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

Researchers have also shown that the same protective molecular complex is present in human blood samples, suggesting that a similar mechanism exists in people. They also used drug compounds to increase HDL3 in the intestine of mice and found that it was protective against various types of liver damage. Although the drug is only available in animal studies, this study treats or prevents liver disease, whether due to intestinal damage from a high-fat diet, alcohol abuse, or physical damage such as surgery. It reveals new possibilities for doing so.

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