'Good cholesterol' may protect liver
Study in mice, human blood samples, suggests HDL from the intestine may prevent liver inflammation

Date:
July 22, 2021
Source:
Washington University School of Medicine
Summary:
The body's so-called good cholesterol may be even better than
we realize.

New research suggests that one 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.



FULL STORY ==========================================================================
The body's so-called good cholesterol may be even better than we
realize. New research from Washington University School of Medicine in
St. Louis suggests that one 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 is published July 23 in the journal Science.

HDL is mostly known for mopping up cholesterol in the body and delivering
it to the liver for disposal. But in the new study, the researchers
identified a special type of HDL called HDL3 that, when produced by the intestine, blocks gut bacterial signals that cause liver inflammation. If
not blocked, these bacterial signals travel from the intestine to the
liver, where they activate immune cells that trigger an inflammatory
state, which leads to liver damage.

"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," said senior author Gwendalyn J. Randolph, PhD, the Emil
R. Unanue Distinguished Professor of Immunology. "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." In the study, the researchers showed that HDL3 from
the intestine protects the liver from inflammation in mice.

Any sort of intestinal damage can impact 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 via the portal vein. The portal vein is the major vessel that
supplies blood to the liver, and it carries most nutrients to the liver
after food is absorbed in the intestine.

Substances from gut microbes may travel along with nutrients from food to activate immune cells that trigger inflammation. In this way, elements
of the gut microbiome may drive 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, a surgical
resident, and Brad W. Warner, MD, the Jessie L. Ternberg PhD, MD,
Distinguished Professor of Pediatric Surgery and chief surgeon at
St. Louis Children's Hospital, both co- authors on the study. Some
premature infants develop a life-threatening condition called necrotizing enterocolitis, an inflammation of the intestine that can require a portion
of the intestine to be surgically removed. Even after a 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 the condition:
They remove a portion of the small intestine in mice and study the
liver fibrosis that results," Randolph said. "There were hints in the literature that HDL might interfere with lipopolysaccharide's detection
by immune cells and that the receptor for lipopolysaccharide might be
linked to liver disease following the bowel surgery.

"However, no one thought that HDL would directly move from the
intestine to the liver, which requires that it enter the portal vein,"
she said. "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 light on different organs and track the HDL from that organ. So,
we wanted to shine 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." As the HDL3 makes
this short journey down 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 blocked from activating immune cells called Kupffer cells.

These are macrophages that reside in the liver and, when activated by lipopolysaccharide, can drive liver inflammation.

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

"We think that LBP, only when bound to HDL3, is physically standing in
the way, so lipopolysaccharide can't activate the inflammatory immune
cells," Han said.

"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." The researchers showed that liver injury is worse when
HDL3 from the intestine is reduced, such as from surgical removal of a
portion of the intestine.



==========================================================================
"The surgery seems to cause two problems," Randolph said. "A shorter
intestine means it's making less HDL3, and the surgery itself leads to an injurious state in the gut, which allows 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, the researchers found that HDL3 was protective, binding to the additional lipopolysaccharide released from the injured intestine and
blocking its downstream inflammatory effects in the liver.

The researchers further showed that the same protective molecular
complexes were present in human blood samples, suggesting a similar
mechanism is present in people. 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 injury.

While the drug is only available for animal research, the study reveals
new possibilities for treating or preventing liver disease, whether it
stems from damage to the intestine caused by high-fat diets, alcohol
overuse or physical injury, such as from surgery.

"We are hopeful 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." ========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Julia
Evangelou Strait. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yong-Hyun Han, Emily J. Onufer, Li-Hao Huang, Robert W. Sprung,
W. Sean
Davidson, Rafael S. Czepielewski, Mary Wohltmann, Mary
G. Sorci-Thomas, Brad W. Warner, Gwendalyn J. Randolph. Enterically
derived high-density lipoprotein restrains liver injury through
the portal vein. Science, 2021; 373 (6553): eabe6729 DOI:
10.1126/science.abe6729 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210722171210.htm

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