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Study in mice, human blood samples, suggests that HDL from the intestines can prevent liver inflammation
Brad W. Warner
The body’s so-called good cholesterol can be even better than we think. New research from the Washington University School of Medicine in St. Louis suggests that a type of high-density lipoprotein (HDL) plays 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 will be published in Science on July 23.
HDL is best known for catching cholesterol in the body and delivering it to the liver for disposal. In the new study, however, the researchers identified a special type of HDL called HDL3 that, when produced by the gut, blocks signals from gut bacteria that cause inflammation of the liver. If not blocked, these bacterial signals travel from the intestines to the liver, where they activate immune cells that trigger an inflammatory state that leads to liver damage.
“Although HDL is considered ‘good cholesterol’, drugs that increase total HDL levels have fallen out of favor in recent years due to clinical studies that have shown no benefit in cardiovascular disease,” said Gwandalyn J. Randolph, PhD, the Emil R. Unanue Distinguished Professor of Immunology. “However, our study suggests that increasing the level of this specific type of HDL, and especially in the gut, promises protection against liver disease, which, like heart disease, is 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 affect how a group of microbes called gram-negative bacteria can affect the body. Such microbes produce an inflammatory molecule called lipopolysaccharide that can travel to the liver through 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 ingested in the intestines. Substances from intestinal microbes can travel along with nutrients from food to activate immune cells that cause inflammation. In this way, elements of the gut microbiome can cause liver disease, including fatty liver disease and liver fibrosis, in which the liver develops scar tissue.
Randolph became interested in this topic through a collaboration with two Washington University surgeons, Emily J. Onufer, MD, resident surgeon, and Brad W. Warner, MD, Jessie L. Ternberg PhD, MD, Distinguished Professor of Pediatric Surgery and Chief Surgeon at St. Louis Children’s Hospital, both co-authors of the study. Some premature babies develop a life-threatening condition called necrotizing enterocolitis, an inflammation of the bowel that requires surgically removing part of the bowel. Even after successful bowel surgery, such babies often develop liver disease, and Onufer and Warner wanted to understand why.
“They looked at this problem in a mouse model of the disease: they remove part of the small intestine in mice and look at the resulting liver fibrosis,” Randolph said. “There was evidence in the literature that HDL could interfere with the detection of lipopolysaccharides by immune cells and that the receptor for lipopolysaccharides could be linked to liver disease after bowel surgery.
“Nobody thought, however, that HDL would travel directly from the intestines to the liver, which requires it to go to the portal vein,” she said. “In other tissues, HDL travels through a different type of vessel called the lymphatic vessel that is not connected to the liver in the intestine. We have a very nice tool in our lab that allows us to illuminate different organs and track the HDL from that organ. So we wanted to illuminate the intestines and see how the HDL exits and where it goes from there. We have shown that HDL3 only exits through the portal vein to go directly to the liver. “
As the 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 are found in the liver and, when activated by lipopolysaccharide, can cause liver inflammation.
As a complex of proteins and fats, HDL3 uses its partnership with LBP to bind to lipopolysaccharides. When LBP is part of the HDL3 complex, it prevents the harmful bacterial molecule from activating the Kupffer cells of the liver and causing inflammation, according to experiments carried out by first author Yong-Hyun Han, PhD, when he was a postdoc in Randolph’s laboratory was. Han is now on the faculty of Kangwon National University in South Korea.
“We believe that only when LBP is bound to HDL3 is it physically in the way so that lipopolysaccharides cannot activate the inflammatory immune cells,” said Han. “HDL3 essentially hides the harmful molecule. However, if LBP binds to lipopolysaccharide and HDL3 is absent, LBP cannot get in the way. Without HDL3, LBP will cause more inflammation. “
The researchers showed that liver damage is worse when HDL3 is reduced from the intestine, for example by surgically removing part of the intestine.
“The operation appears to be causing two problems,” Randolph said. “A shorter intestine means less HDL3 is produced, and the operation itself damages the intestine, which allows more lipopolysaccharide to pass into the portal vein blood. If you remove the part of the intestine that produces the most HDL3, you will get the worst liver result. If you have a mouse that can’t genetically make HDL3, the hepatitis is worse too. We also wanted to see if this dynamic was present in other forms of bowel injury, so we looked at mouse models of a high fat diet and alcoholic liver disease. ”
In all of these intestinal injury models, the researchers found that HDL3 was protective, binding to the extra lipopolysaccharide released from the injured intestine and blocking its downstream inflammatory effects in the liver.
The researchers also 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 to increase HDL3 in the intestines of mice and found that it protects against various types of liver damage. While the drug is only available for animal testing, the study shows new ways to treat or prevent liver disease, be it intestinal damage from a high-fat diet, alcohol abuse or physical injuries such as surgery.
“We hope that HDL3 can serve as a target for future therapies for liver disease,” said Randolph. “We are continuing our research to better understand the details of this unique process.”
This work was supported by the National Institutes of Health (NIH) Grant Numbers R01DK119147, AI0499653, T32DK077653, RO1HL127649, and HL138908; a Primary Nursing Supplement, partially supported by the National Research Foundation of Korea, number 2021R1C1C1004023; an American Heart Association Career Development Award, number AHA: 1,8CDA34110273; and the Lawrence C. Pakula, MD, IBD Research Fellowship. Further support from the core facility was provided by the Digestive Diseases Research Core Center at Washington University, Grant Number P30 DK052574; Washington University Center for Cellular Imaging (WUCCI) at Washington University’s Children’s Discovery Institute, numbers CDI-CORE-2015-505 and CDI-CORE-2019-813; the Foundation for Barnes-Jewish Hospital to Washington University Proteomics Shared Resource, Grant No. 3770; from the WU Institute of Clinical and Translational Sciences, grant number NCATS UL1 TR000448; the Mass Spectrometry Research Resource, Grant Numbers NIGMS P41 GM103422 and R24GM136766; the Siteman Comprehensive Cancer Center, Grant Number NCI P30 CA091842; the Genome Technology Access Center through an NCI Cancer Center Grant number P30 CA91842 and ICTS / CTSA Grant number UL1TR002345 from the National Center for Research Resources.
Han YH, Onufer EJ, Huang L, Sprung RW, Davidson WS, Czepielewski RS, Wohltmann M, Sorci-Thomas MG, Warner BW, Randolph GJ. Enterically obtained high-density lipoprotein inhibits liver damage via the portal vein. Science. July 23, 2021.
The 1,500 faculty physicians at Washington University School of Medicine are also the medical staff for the Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care and consistently ranks among the top medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its affiliation with Barnes-Jewish and St. Louis Children’s Hospital.