Hepatokines and Metabolic Dysregulation in Chronic Disease

The liver has emerged as a central regulator of systemic metabolism through its secretion of bioactive proteins known as hepatokines. These factors—among them fibroblast growth factor 21 (FGF21), fetuin-A, fetuin B and others—mediate cross-talk between hepatic, adipose, muscle and pancreatic tissues. In the setting of fatty liver and metabolic stress, altered hepatokine profiles drive insulin resistance, low-grade inflammation and dyslipidaemia, establishing a pathogenic link between Metabolic Steatotic Liver Disease and extrahepatic complications such as type 2 diabetes, cardiovascular disease and chronic kidney disease. Mechanistic studies reveal that fetuin-A impairs insulin receptor signalling, FGF21 modulates energy expenditure and lipid oxidation, and fetuin B activates inflammatory programmes in adipose tissue. Advances in multi-omics profiling, in vivo models and genetic approaches have refined our understanding of causality and identified hepatokine networks as potential biomarkers and therapeutic targets. Clinically, agents that modulate hepatokine activity—ranging from FGF21 analogues to novel dual incretin agonists—hold promise for restoring metabolic homeostasis. The global rise in obesity, diabetes and fatty liver disease underscores the need for interventions that address hepatokine-driven pathways to prevent progression of chronic metabolic disorders.

Research from Nature Portfolio

Recent genetic analyses using Mendelian randomisation in large population cohorts have established that higher circulating fetuin-A levels increase the risk of developing type 2 diabetes. Furthermore, the impact of fetuin-A on coronary artery disease is modified by diabetic status, with elevated levels exacerbating risk in individuals with diabetes, while sex-specific analyses reveal a protective effect against myocardial infarction in women. These findings strengthen the causal link between fetuin-A and cardiometabolic dysregulation and suggest that quantifying fetuin-A could improve prediction of diabetes onset and vascular complications.

Hepatokines and Metabolic Dysregulation in Chronic Disease publication trend

The graph below shows the total number of articles in hepatokines and metabolic dysregulation in chronic disease across all publications each year (not limited to Nature Index journals).

Technical terms

Hepatokine: A liver-secreted protein that influences glucose, lipid and energy metabolism in distant tissues.

Insulin resistance: A diminished cellular response to insulin, leading to impaired glucose uptake and hyperglycaemia.

Fibroblast growth factor 21 (FGF21): A hepatokine that enhances energy expenditure, improves lipid profile and ameliorates glucose homeostasis.

Fetuin-A (AHSG): A multifunctional glycoprotein from the liver that inhibits insulin receptor signalling and regulates calcification.

Fetuin B: A hepatokine that links hepatic steatosis to adipose inflammation and systemic glucose intolerance.

Metabolic Steatotic Liver Disease (MASLD): A term emphasizing the metabolic dysfunction underlying fatty liver and its systemic effects.

References

1. Hepatokines and MASLD: The GLP1-Ras-FGF21-Fetuin-A Crosstalk as a Therapeutic Target. International Journal of Molecular Sciences (2024).
2. Fetuin B in white adipose tissue induces inflammation and is associated with peripheral insulin resistance in mice and humans. Obesity (2023).
3. Fetuin-A and its genetic association with cardiometabolic disease. Scientific Reports (2023).