What Is a Hepatokine? Definition and What Research Reports

Plain-language definition

A hepatokine is a protein or peptide that is made and secreted by liver cells — chiefly hepatocytes — and released into the bloodstream, where it can act on tissues far from the liver. The term is a category label rather than the name of any single molecule: it groups together liver-derived secreted factors in the same way that adipokine groups fat-derived factors and myokine groups muscle-derived factors. Reviews of the field have framed the liver as an endocrine organ whose secreted proteins participate in crosstalk with adipose tissue, skeletal muscle, the pancreas and the central nervous system, and have catalogued hepatokines in the context of non-alcoholic fatty liver disease (PMID 36754018). This page is for educational purposes only and is not medical advice; consult a licensed physician for questions about health, diagnosis or treatment.

What class of molecule is it?

Hepatokines are secreted proteins and peptides. Most are translated in hepatocytes, processed through the secretory pathway, and exported into plasma, where they circulate at concentrations that can be measured by immunoassay. Some are small enough to be described as peptide hormones; others are larger glycoproteins or growth-factor-family proteins. What unites them is source and destination — liver origin, systemic circulation, receptor-mediated action elsewhere — not size or fold.

Because the definition rests on tissue of origin, the same molecule can carry more than one label. FGF21, for example, is expressed in several tissues but is classified as a hepatokine when discussed as a liver-derived circulating factor, and it was described in that role in work on metabolic dysfunction-associated steatotic liver disease (MASLD) progression (PMID 38894596). Reviews covering both fat- and liver-derived signals in MASLD have discussed adipokines and hepatokines side by side for exactly this reason (PMID 40868109).

Where the term is used

The word appears most often in three research contexts:

• Metabolic liver disease. Hepatokines are studied as mediators and markers in NAFLD/MASLD, the spectrum of fat accumulation, inflammation and fibrosis in the liver (PMID 36754018).
• Inter-organ signalling. Papers use the term when describing how liver-derived molecules influence insulin sensitivity, energy intake or inflammation in other tissues (PMID 40868109).
• Biomarker discovery. Circulating hepatokines have been evaluated alongside adipokines as blood-based diagnostic markers during obesity therapy (PMID 36430499).

How the term is used in peptide research

In peptide literature, "hepatokine" functions as a classification, not as a description of a product or protocol. When a paper calls a molecule a hepatokine, it is stating where the molecule comes from and that it acts as a circulating signal. Several hepatokines — FGF21 and GDF15 among them — are also the biological templates for engineered analogues studied in metabolic research, which is why the category name turns up in peptide-adjacent reading. The label itself carries no claim about safety, availability or human use; it only situates the molecule within liver endocrinology.

Commonly cited examples

Broader reviews list additional candidate hepatokines beyond these four and discuss how the set overlaps with adipose-derived signalling molecules in MASLD (PMID 40868109).

What the published literature reports

Most of the evidence base is preclinical or observational. A 2023 review in Cell Metabolism summarised the role of hepatokines in NAFLD, positioning liver-secreted factors as participants in the disease's inter-organ signalling network (PMID 36754018). In animal work, researchers reported that hepatocyte-specific GDF15 overexpression improved high-fat-diet-induced obesity and hepatic steatosis in mice, and attributed the effect in part to induction of hepatic FGF21 (PMID 39402176). Separately, the study of FNDC4 reported reduced hepatocyte inflammatory cell death through an AMPKα-dependent mechanism in metabolic dysfunction-associated steatotic liver disease (PMID 39173437).

Regulation of hepatokine output has also been examined. Researchers reported that lipopolysaccharide stimulation altered LECT2 expression in hepatocytes through TLR4 signalling, linking an inflammatory input to a hepatokine output (PMID 40495481). On the human side, FGF21 was reported to be a hepatokine involved in MASLD progression (PMID 38894596), and a 2022 analysis reported that circulating adipokines and hepatokines served as diagnostic markers during obesity therapy (PMID 36430499).

Hepatocyte secretory biology: what studies report

Research on hepatocytes has not been limited to the proteins they release. A 2026 Cell Metabolism report described lipid-induced granules in hepatocytes and reported that these granules alleviated liver fibrosis (PMID 41519131). Work of this kind sits adjacent to hepatokine research because it concerns how hepatocytes package and handle material that influences the surrounding liver environment.

How hepatokines are measured

Because hepatokines circulate, they are typically quantified in serum or plasma. Study designs in this area generally compare concentrations between groups — for instance across stages of fatty liver disease or before and during an intervention — and correlate them with imaging, histology or metabolic measures. The 2022 marker analysis took this approach in the setting of obesity therapy and reported that circulating adipokines and hepatokines functioned as diagnostic markers (PMID 36430499). Reviews have noted that hepatokine panels remain a developing area rather than a settled clinical tool in MASLD (PMID 40868109).

Limits of the term

Three caveats recur in the literature. First, the classification is source-based, so a molecule may be a hepatokine in one paper and a myokine or adipokine in another depending on the tissue under study. Second, much of the mechanistic evidence comes from rodent and cell models — the GDF15 and FNDC4 findings above were reported in such systems (PMID 39402176, PMID 39173437). Third, a circulating concentration that tracks with disease does not establish that the molecule causes the disease; reviews of hepatokines in NAFLD have discussed this distinction explicitly (PMID 36754018).

Related terms

• Adipokine — a signalling protein secreted by adipose tissue; discussed alongside hepatokines in MASLD reviews (PMID 40868109).
• Myokine — a signalling protein secreted by skeletal muscle.
• NAFLD / MASLD — overlapping terminology for fatty liver disease; the setting in which most hepatokine research has been reported (PMID 38894596).
• Inter-organ crosstalk — the broader concept that secreted factors coordinate metabolism across tissues (PMID 36754018).

References

• The role of hepatokines in NAFLD (Cell Metabolism, 2023)
• Hepatocyte-specific GDF15 overexpression improves high-fat diet-induced obesity and hepatic steatosis in mice via hepatic FGF21 induction (Scientific Reports, 2024)
• FNDC4 reduces hepatocyte inflammatory cell death via AMPKα in metabolic dysfunction-associated steatotic liver disease (Clinical Nutrition, 2024)
• Lipid-induced granules in hepatocytes alleviate liver fibrosis (Cell Metabolism, 2026)
• Fibroblast growth factor 21 is a hepatokine involved in MASLD progression (United European Gastroenterology Journal, 2024)
• LPS stimulation-induced regulation of LECT2 expression via TLR4 in hepatocytes (BMB Reports, 2025)
• Circulating Adipokines and Hepatokines Serve as Diagnostic Markers during Obesity Therapy (International Journal of Molecular Sciences, 2022)
• Adipokine and Hepatokines in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Current and Developing Trends (Biomedicines, 2025)