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USA: Therapies for Liver Disease Good Cholesterol May Be Even Better Than We Thought

Editor: Alexander Stark

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.

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First author Yong-Hyun Han, PhD, (left) and co-author and Washington University surgical resident Emily Onufer, MD, work in the surgical suite where the mouse surgeries were conducted as part of this study.
First author Yong-Hyun Han, PhD, (left) and co-author and Washington University surgical resident Emily Onufer, MD, work in the surgical suite where the mouse surgeries were conducted as part of this study.
(Source: Brad W. Warner)

Washington/USA — HDL is mostly known for mopping up cholesterol in the body and delivering it to the liver for disposal. But in a new study, 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.

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.

Gwendalyn J. Randolph

In the study, the researchers showed that HDL3 from the intestine protects the liver from inflammation in mice.

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.

“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.”

References: Han YH, Onufer EJ, Huang L, Sprung RW, Davidson WS, Czepielewski RS, Wohltmann M, Sorci-Thomas MG, Warner BW, Randolph GJ. Enterically derived high-density lipoprotein restrains liver injury via the portal vein. Science. July 23, 2021.

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