New target that allows cholesterol to be excreted directly in the feces

Cholesterol, an essential component for building cells, is also a "prime suspect" for cardiovascular disease (CVD)—high levels of cholesterol in the blood are an important risk factor for CVD.

There are three main types of hypolipidemic drugs on the market today—statins, ezetimibe, and PCSK9 inhibitors. Each of these drugs has its own ability to lower blood lipid levels by different mechanisms.

• Statins: reduce cholesterol synthesis and enhance low-density lipoprotein (LDL) absorption
• Ezetimibe: inhibits the absorption of cholesterol in the intestine
• PCSK9 inhibitors: enhance the absorption of LDL by the liver

Professor Song Baoliang's team at Wuhan University has found a more direct way to reduce fat—bowel movements. They discovered that inhibiting the expression of the hepatocyte membrane protein ASGR1 prevented lipogenesis and encouraged cholesterol efflux into bile, which was then eliminated from the body through feces, lowering blood and liver lipid levels.

Their findings were published in Nature recently entitled "Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion".

ASGR1 is a specific protein receptor found on hepatocyte membranes, which recognizes and binds to desialic acid glycoproteins in the blood and mediates endocytosis to "capture" them and deliver them to intracellular lysosomes for degradation.

Large-scale human genomics research published in 2016 linked ASGR1 to lipid lowering. The study found that a loss-of-function mutation in the Asgr1 gene was linked to reduced cholesterol levels and a lower risk of CVD. Animal studies later confirmed that removing ASGR1 protein expression can reduce blood cholesterol levels. However, no one has yet discovered the mechanism by which ASGR1 protein deletion lowers lipid levels.

Therefore, to explore what role ASGR1 plays in lipid metabolism, Song Baoliang's team conducted this study.

They first knocked down the Asgr1 gene in a human hepatoma cell line (Huh7) and found that genes related to the cholesterol efflux signaling pathway mediated by protein LXR were significantly enriched and the expression of ABCG5 and ABCG8, key target proteins of LXR, was significantly upregulated. In contrast, LXR, ABCG5, and ABCG8 expression were down-regulated when ASGR1 was overexpressed.

In terms of changes in cholesterol levels, ASGR1-deficient mice had greatly reduced cholesterol levels in the blood as well as in the liver, while cholesterol levels in the bile were significantly increased. The cholesterol levels in the bile of ASGR1-deficient mice were increased by 114% compared to wild-type mice. Further studies showed that the hypolipidemic effect mediated by ASGR1 deletion was dependent on LXR. This implies that ASGR1 deletion is associated with the promotion of cholesterol efflux.

In addition, the researchers noted that ASGR1-deficient mice had significantly lower levels of cholesterol synthesis-related proteins in the liver and no significant changes in LDL receptor levels, suggesting that ASGR1 may have other means of cholesterol remediation.

Following these hints, the researchers refined the routes by which ASGR1 modulates lipid metabolism.

ASGR1, located on the hepatocyte membrane, binds to salivary glycoproteins in the blood and delivers them to lysosomes for degradation via lattice-protein-mediated endocytosis. The amino acids released after glycoproteins are digested regulate cholesterol metabolism by the mTORC1/AMPK signaling pathway.

Once ASGR1 is absent, it inhibits the mTORC1 signaling pathway and activates the AMPK signaling pathway in hepatocytes. As a result, on the one hand, cholesterol regulatory element binding protein (SREBP) expression is inhibited, thereby reducing cholesterol production; on the other hand, LXR protein expression is upregulated and cholesterol efflux-related pathways are enriched, promoting cholesterol efflux into bile and excretion into the body via feces.

In this way, ASGR1 deficiency is inhibiting cholesterol production, and perhaps ASGR1 is a good potential therapeutic target for lipid lowering.

To demonstrate this, the researchers employed siRNA interference technology to target and reduce ASGR1 expression in mice, and they observed a drop in blood cholesterol levels and an increase in bile cholesterol levels, as well as better atherosclerosis in mice induced by a high-fat diet.

In addition, the researchers developed an antibody (4B9-IgG) targeting ASGR1 and validated its lipid-lowering effect in a series of mouse experiments.

The results showed that wild-type mice receiving intraperitoneal injection of anti-ASGR1 antibody:

• 50% reduction in total serum cholesterol levels and a significant reduction in liver cholesterol
• 62% increase in bile volume in the gallbladder and more than 1-fold increase in bile cholesterol levels
• Increase in fecal cholesterol levels by approximately 87%.

Notably, for ASGR1-deficient mice, treatment with anti-ASGR1 antibodies resulted in few alterations, including various in vivo metabolic responses, confirming the specificity of anti-ASGR1 antibodies. Also, no other metabolic alterations or liver injuiries were detected in wild-type mice after treatment.

Finally, the investigators observed a synergistic effect of anti-ASGR1 antibodies in combination with statins and ezetimibe in mice experiments, again demonstrating the therapeutic significance of anti-ASGR1 antibodies.

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