Antibody shows promise against obesity-related liver disease and atherosclerosis in mice

Tuesday, October 29, 2024

An antibody called bFKB1 improves liver disease and atherosclerosis in a mouse model of metabolic dysfunction-associated steatohepatitis (MASH), which is associated with obesity. The antibody also decreased body weight and improved inflammation and insulin sensitivity. Learning how the antibody exerts these effects could someday lead to development of a new drug to fight MASH, according to research that was published in The FASEB Journal.

MASH is a complication of metabolic syndrome in which fat builds up in the liver. It is a main cause of liver damage in the U.S. and can lead to liver scarring and dysfunction. In addition, studies have shown that MASH patients are at high risk for developing atherosclerosis and cardiovascular disease. So far, only one drug has been approved by the U.S. Food and Drug Administration to treat the condition. 

A promising MASH target is the hormone FGF21. This molecule reduced body weight and glucose and lipid levels in animal and human trials, and similar molecules called FGF21 analogues also have had positive results. The antibody bFKB1 is one of these analogues. Whereas antibodies typically are inhibitors, this one is an activator, causing similar effects to FGF21. bFKB1 is more specific than other FGF21 analogues, so it could have less severe side effects. Studying bFKB1 could help researchers develop new and better treatments for MASH.

In previous animal tests, bFKB1 improved metabolism and decreased body weight, so José Inia and colleagues at The Netherlands Organization for Applied Scientific Research (TNO), Leiden University Medical Centre, Genentech Inc., and the Netherlands Heart Institute took the next step and tested bFKB1 in a MASH mouse model called Ldlr-/-.Leiden that also develops atherosclerosis. The way that MASH develops in these mice is very similar to how it develops in human patients. 

While on a high-fat diet, the mice received either a weekly dose of a control antibody or bFKB1. Compared with controls, MASH mice treated with bFKB1 lost weight and fat mass while sometimes even eating more food. “That result felt contradictory,” says Inia. “But when we looked further, we saw that the adipose tissue was browning, indicating an increased energy expenditure.” In addition, bFKB1 mice had improved insulin sensitivity and reduced cholesterol and triglyceride levels. Reduced atherosclerosis and less severe lesions were also observed in bFKB1 versus control animals.

Other signs pointed toward improved liver health for bFKB1 mice. Expression was boosted for genes involved in lipid metabolism pathways and in the inactivation of inflammation and fibrosis in the livers of bFKB1 mice. Using microscopy, the researchers observed less fatty build-up and inflammation in the livers of bFKB1 mice than in controls. In the study, both sets of mice already developed MASH before treatment, so they started out with some liver scarring and collagen accumulation. By the end of the study, collagen levels were similar in both groups. “Although fibrosis was already present, we found that new formation of collagen was reduced in bFKB1 mice,” says Hans Princen, senior scientist at TNO. “We concluded that perhaps if we had prolonged the study, we would have seen an effect on fibrosis.” 

Overall, bFKB1 treatment enhanced the health of MASH mice. “With this compound, we can target the liver, but also the adipose tissue and cardiovascular disease, which I think is a very holistic approach to such a big problem,” says Inia.

Funding: Genentech Inc., TNO 

Conflict of interest statement: Three of the authors are employees of Genentech Inc. One author is a former employee of Genentech Inc. and is a present employee of Takeda Pharmaceuticals. See the paper for the full statement. 

Read the full article, “Therapeutic effects of FGF21 mimetic bFKB1 on MASH and atherosclerosis in Ldlr-/-.Leiden mice,” published in The FASEB Journal.