World Hepatitis Day: High-density lipoprotein cholesterol produced in the intestine protects the liver from inflammation

July 28 is World Hepatitis Day.
Viral hepatitis is an inflammation of the liver that can cause severe liver disease and hepatocellular carcinoma
.

This year’s theme is "No Waiting for Elimination of Hepatitis"

Recently, scientists at the University of Washington School of Medicine have shown that a high-density lipoprotein (HDL) produced by the intestine plays a previously unknown role in protecting the liver from damage
.

The team’s research shows that this high-density lipoprotein called HDL3 protects the liver by blocking the inflammatory signals produced by common intestinal bacteria

Dr.
Gwendalyn J.
Randolph, Emil R.
Unanue, a famous professor of immunology, said: "Although HDL is considered to be a'good cholesterol', clinical trials have shown no benefit to cardiovascular disease.
Drugs that increase the overall level of HDL It has lost favor in recent years
.

" "But our research shows that increasing the level of this specific type of high-density lipoprotein (HDL), especially increasing the level of high-density lipoprotein in the intestine, may be expected to prevent liver disease

High-density lipoprotein cholesterol (HDL-c) is mainly used to remove cholesterol in the body and transport it to the liver for processing
.

But the author explained that HDL may also have anti-inflammatory or antibacterial activity through interactions with different plasma proteins

Any form of intestinal damage will affect the impact of Gram-negative bacteria on the body
.

These bacteria produce the inflammatory molecule lipopolysaccharide, which can reach the liver through the portal vein

One of the obstacles to considering the potential role of intestinal HDL in the team's term gut-liver axis is the relative lack of knowledge about how intestinal-derived HDL is actually delivered to the liver
.

They pointed out: "HDL is usually mobilized from tissues through lymphatic vessels, rather than from the intestine to the liver

In their new study, the researchers found that HDL3 produced in the intestine reaches the liver through the portal vein, rather than through the lymphatic system in the intestine.
This finding suggests that HDL3 may have the ability to protect the liver
.

They wrote: ".

The latest reported research shows that the HDL3 produced in the intestine can indeed protect the liver of mice from inflammation by blocking the bacterial-derived LPS
.

Randolph worked with two Washington University surgeons Emily J.

Some premature babies suffer from a fatal disease, necrotizing enterocolitis, which is an inflammation of the intestines that requires surgery to remove part of the intestine
.
Even after successful bowel surgery, affected babies may often develop liver disease, and Onufer and Warner want to understand why
.

Randolph explained: "They studied this problem in a mouse model: They removed a portion of the small intestine of the mouse and studied the resulting liver fibrosis
.
" "There are indications in the literature that HDL may interfere with the ability of immune cells to treat lipid Detection of polysaccharides, and lipopolysaccharide receptors may be related to liver disease after intestinal surgery
.

 

"However, no one thinks that HDL will move directly from the intestine to the liver, which requires it to enter the portal vein," she continued
.
In other tissues, high-density lipoproteins are excreted through a different type of blood vessel-lymphatic vessels, which are located in the intestine and are not connected to the liver
.
There is a very good tool in our laboratory, which can let light shine on different organs and track the high-density lipoprotein of that organ
.
So, we want to illuminate the intestines with light and see how HDL leaves and where it goes from there
.
This is how we proved that HDL3 only enters the liver directly through the portal vein
.
"

 

When HDL3 makes this short journey along the portal vein, it binds to a protein called lipopolysaccharide binding protein (lbp), which binds to harmful lipopolysaccharides
.
The harmful lipopolysaccharides bound to this complex are prevented from activating a type of immune cell called Kupffer cells (KCs)
.
These macrophages reside in the liver and, when activated by lipopolysaccharide, can drive liver inflammation
.
Therefore, as a complex of protein and fat, HDL3 uses its partnership with LBP to bind to LPS
.
When Lycium barbarum polysaccharide HDL3 is part of the complex, it prevents harmful bacterial molecules from activating liver Kup cells and inducing inflammation.
Faculty
.

"We believe that only when LBP binds to HDL3 will it physically block it, so lipopolysaccharide cannot activate inflammatory immune cells," Han said
.
"HDL3 essentially hides harmful molecules
.
However, if LBP binds to lipopolysaccharide and HDL3 is not present, LBP cannot prevent the formation of lipopolysaccharide
.
Without HDL3, LBP will cause stronger inflammation
.
" The author further concluded: "We It is shown here that the intestine produces a small HDL called HDL3, which is enriched in LBP
.
This high-density lipoprotein is transported to the liver through the portal vein
.
When it reaches the portal vein blood, it has been compounded with LBP, and it The carried LPS is masked so it does not bind to liver KCs, thereby bypassing the induction of pro-inflammatory and pro-fibrotic genes
.
The location of the intestinal epithelium where HDL is produced allows the localization of LPS to be captured before it enters downstream tissues
.
"

Researchers also found that when HDL3 in the small intestine is reduced, liver damage is more serious, for example, as a result of surgical removal of part of the small intestine
.
Randolph said: "Surgery seems to cause two problems
.
" A shorter intestine means less HDL3 is produced.
The operation itself can cause damage to the intestine, which allows more lipopolysaccharide to overflow into the portal blood
.
When you remove the part of the intestine that produces the most HDL3, your liver will get the worst results
.
When you have a mouse genetically unable to produce HDL3, liver inflammation will also be more severe
.
We also wanted to see if this dynamic also exists in other forms of intestinal damage, so we looked at mouse models of high-fat diet and alcoholic liver disease
.
"

In all these intestinal injury models, the researchers found that HDL3 has a protective effect.
It binds to extra lipopolysaccharides released from the damaged intestine and blocks its downstream inflammatory effects in the liver
.
".
.
.
The small intestine produces HDL3?" Protects the liver from inflammation and fibrosis.
The conditions observed in various mouse liver injury models are similar to the clinically relevant conditions in humans, including small bowel surgical resection, alcohol consumption or high-fat diet.
"The scientists said
.
They further showed that the same protective molecular complex also exists in human blood samples, which suggests that a similar mechanism exists in humans
.

Interestingly, in further experiments, the team also used a drug compound to increase HDL3 in the intestines of mice, and found that this has similar protective effects against different types of liver damage
.
The author explained: “Oral drugs that target the transcription factor liver X receptor (the main regulator of HDL biogenesis-related genes) can increase intestinal HDL levels and protect mice from liver pathology
.
” “If the mice don’t Expressing intestinal-derived HDL loses this protection, indicating that intestinal HDL is a key target of the drug
.
"

Although this medicinal compound is only used in animal studies, this research reveals new possibilities for the treatment or prevention of liver disease, whether it is caused by a high-fat diet, alcoholism, or physical injury such as surgery
.
The authors further concluded, “Therefore, intestinal HDL may be a suitable pharmacological target for protecting the liver from leakage of intestinal LPS in alcoholic and non-alcoholic environments
.
”

Randolph said: "We hope that HDL3 can be used as a target for the treatment of liver disease in the future
.
" "We are continuing to research to better understand the details of this unique process
.
"