While most people know about the dangers of high cholesterol, that’s only half of the story. The body also contains a “good” cholesterol called high-density lipoprotein (HDL), and animal research suggests HDL has another role in protecting the liver from injury.
HDL helps the body by absorbing cholesterol and delivering it to the liver. The liver then flushes the cholesterol out of the body. But in the current study, researchers from the Washington University School of Medicine reveal that a form of HDL, known as HDL3, protects against liver inflammation by blocking inflammatory signals from gut bacteria. If the signals are not blocked, they can travel from the intestine to the liver where they activate immune cells to promote inflammation.
Too much inflammation has the potential to cause liver damage such as fatty liver disease or liver fibrosis.
“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,” says senior author Gwendalyn J. Randolph, PhD, the Emil R. Unanue Distinguished Professor of Immunology at Washington, in a university release. “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 team observed how HDL3 from the intestine protected the liver from inflammation in mice. When there is any type of intestinal damage, it can trigger gram-negative bacteria to respond with an inflammatory molecule called lipopolysaccharide. The molecule moves to the liver through the portal vein. While it’s traveling, the molecule can activate immune cells to start the inflammatory process.
The team noticed the process is similar to a life-threatening condition seen in premature babies called necrotizing enterocolitis, where doctors need to surgically remove an inflamed intestine. Even if the intestine is partially resected, babies can go on to develop liver disease.
To replicate the situation, the researchers removed some of the small intestine and studied the eventual liver fibrosis. Previous research has suggested that HDL could disrupt lipopolysaccharide’s triggering of the immune cell response and that the receptor for lipopolysaccharide could be associated with liver disease.
The team was surprised to find how involved HDL was in disrupting inflammation from gram-negative bacteria. “However, no one thought that HDL would directly move from the intestine to the liver, which requires that it enter the portal vein,” Dr. Randolph explains. She says HDL travels through a lymphatic vessel in the intestine in other tissue and this vessel is not connected to the liver. But when the team tracked HDL they found it does enter the portal vein to arrive at the liver.
While it travels to the liver via the portal vein, HDL3 binds to the lipopolysaccharide binding protein which binds the molecule itself. Once bound, it is prevented from activating immune cells called Kupffer cells from causing 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,” says lead author Yong-Hyun Han, PhD, a former postdoctoral researcher in Dr. Randolph’s lab and now a faculty member at Kangwon National University in South Korea. “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.”
When HDL3 levels are reduced from surgical removal of the intestine, the team found liver injury gets worse. The team explains that the liver injury becomes more serious because the shorter intestine is making less HDL3. Additionally, surgery itself is trauma to the body and injuring the gut gives lipopolysaccharide more opportunity to spill into 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,” says Dr. Randolph.
Additional studies also showed that HDL3 could also protect against other forms of liver injury. In their animal research, a drug compound that increased HDL3 in mices’ intestines protected against further liver injury damage. The drug in the future could potentially help treat or prevent liver disease caused by alcohol abuse, high-fat diets, or surgeries.
“We are hopeful that HDL3 can serve as a target in future therapies for liver disease,” Dr. Randolph says. “We are continuing our research to better understand the details of this unique process.”
The study is published in the journal Science.