Hepatokines

Hepatokines are liver-derived secreted proteins that act as hormones or signaling molecules to regulate metabolism in distant organs. They include cytokines, hormones, and growth factors produced primarily by hepatocytes and liver-resident cells, and they influence processes in adipose tissue, skeletal muscle, pancreas, and brain to coordinate systemic energy homeostasis. Dysregulation of hepatokine signaling is linked to metabolic conditions such as obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD).

Liver-derived signals are produced in response to nutritional state, insulin signaling, inflammation, and liver injury. The secretion and activity of hepatokines can vary with fatty liver accumulation, obesity, or metabolic stress, and their effects are often context-dependent, with potential pro- or anti-inflammatory and pro- or anti-diabetic outcomes depending on tissue and metabolic milieu.

Well-characterized examples include FGF21, a hepatokine that acts on adipose tissue and the brain to improve insulin sensitivity, promote fatty acid oxidation, and suppress lipogenesis. Fetuin-A (AHSG) is associated with insulin resistance and inflammation and can activate inflammatory pathways in adipose tissue. Selenoprotein P (SEPP1) is linked to impaired insulin signaling and increased hepatic glucose production in obesity. Angiopoietin-like proteins such as ANGPTL3 and ANGPTL8, produced by the liver, regulate plasma triglyceride metabolism by modulating lipoprotein lipase activity. Fetuin-B is another hepatokine under investigation for roles in glucose metabolism, though its functions are not as well defined.

Clinically, hepatokines are studied as biomarkers of liver metabolic state and as potential therapeutic targets. Altered hepatokine signaling contributes to systemic metabolic dysfunction, and therapies aiming to modify hepatokine levels or action are an active area of research in metabolic liver diseases.