Dual action hormones show hope in reversing fatty liver disease

According to new research published in cell metabolism, hormones that occur naturally in the body may be the key to solving one of the most common liver diseases in the world.

Scientists have found that fibroblast growth factor 21 (FGF21) can reverse metabolic dysfunction-related steatohepatitis (MASH) through complex coordination between the brain and the liver.

MASH affects millions of people worldwide and is an incremental form of metabolic dysfunction-associated fat-schizolid liver disease (MASLD), which affects approximately 40% of adults worldwide. Despite the high rate, treatment options are still limited.

Their findings by Jesse P. Rose and Matthew J. revealed a dual action mechanism that could provide more effective treatments for patients with this increasingly common liver disease.

“We demonstrate that the beneficial metabolic effect of FGF21 on reverse mashing is mediated through different mechanisms to independently reduce hepatic triglyceride and cholesterol levels,” the researchers noted in the paper.

The study found that FGF21 operates through two different pathways. First, it signals glutamategic neurons in the central nervous system, which stimulates the reduction of triglycerides in the liver and reverses fibrosis. Second, it acts directly on hepatocytes (hepatocytes) to lower cholesterol levels.

The team used a mouse model of diet-induced mashed potatoes to find that FGF21 administration significantly improved liver health. Treatment lowers triglyceride and cholesterol levels in the liver, reduces markers of hepatocyte damage, and reverses collagen deposition of liver fibrosis.

Interestingly, brain-hepatic connections proved to be crucial for the effectiveness of FGF21. Hormones increase sympathetic activity on the liver, thereby inhibiting the liver’s ability to produce new fats through a process called de novo fat production. When researchers blocked this brain communication to spread, FGF21 lost its ability to lower triglyceride levels.

The discovery that FGF21 affects hepatic cholesterol levels surprised the researchers because previous studies have shown that hormones do not signal directly to hepatocytes. However, this study found that FGF21 promotes cholesterol movement from the liver to the bile by increasing the expression of transporters ABCG5 and ABCG8.

These findings emerged at a critical moment, as Mash represents an increasing public health concern. The disease is characterized by excessive lipid deposition in the liver, which can develop into inflammation, hepatocyte death and fibrosis. If untreated, these changes can increase the risk of cirrhosis, liver failure and hepatocellular carcinoma.

Dr. Potthoff and colleagues noted that MASH is reversible before the onset of cirrhosis, which makes it “targeted through pharmacological interventions.”

This study is of great significance to drug development. Several FGF21-based analogues have shown encouraging results in clinical trials of human MASLD and MASH. For example, once-weekly Efruxifermin (a bivalent FGF21-FC fusion protein) or PEGOZAFERMIN (a sugar-phosphorylated FGF21 analogue) improves liver fibrosis in patients with biopsy-verified mixtures.

However, new insights on the mechanism of dual action may help refine these treatments. Understanding that FGF21 works through both the brain and liver pathways may lead to more targeted treatments with fewer side effects.

The team warned that while their findings in mice were promising, further studies are needed to confirm whether they are suitable for humans. Furthermore, questions remain about how different doses of FGF21 affect hepatocyte and neuronal signaling, and whether specific effects of FGF21-mediated sympathetic activity of MASH are required on the liver.

However, the study provides valuable insights into what the authors call “a promising pharmacological target for the treatment of mud”, which gives millions of hope for the effects of this increasingly common liver disease.