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General Information

Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Hepatokines can influence metabolic processes through autocrinem paracrinem and endocrine signaling. (https://www.nature.com/articles/nrendo.2017.56) Hepatokines can also be referred to as hepatocytes-derived cytokines. (https://mtodjournal.net/article/view/5573) Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. (https://pubmed.ncbi.nlm.nih.gov/34944728/) Many hepatokines and several signaling proteins have been linked to diseases of other organs, such as the heart, muscle, bone, and eyes. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847667/) Hepatocytes secrete more than 560 types of hepatokines, many of which regulate metabolic and inflammatory diseases in the liver or at distant organs (e.g. the endocrine roles of hepatokines in bone and heart tissues) through circulation delivery 6. Under extreme challenges, such as long-term starvation or overnutrition, the liver may secrete hepatokines to influence energy homeostasis and inflammation. Indeed, if the liver is unable to fulfill this process, the corresponding disease develops, such as steatosis from impaired hepatic insulin-sensitizing substance production . Hepatokines signal energy status and help regulate nutrient availability to multiple peripheral tissues and the central nervous system (CNS) (https://www.sciencedirect.com/science/article/pii/S221287782030212X)hepatocytes can secrete multiple hepatokines into the blood. In particular, these hepatokines, similar to hypothalamic hormones and insulin, are structurally polypeptides, and proteins and are transcribed and expressed by specific genes (that are not synthesized through biochemical reactions). However, it should be noted that the substances secreted by traditional endocrine cells are tissue-specific. Insulin is mainly secreted by pancreatic beta cells, and thyroid hormone can only be secreted by thyroid follicular epithelial cells.https://mtodjournal.net/article/view/5573 hepatokines have been described to be involved in the regulation of energy and nutrient metabolism by acting directly on the liver or on distal target tissues (Table 1). These proteins regulate glucose and lipid metabolism in the liver but also in the skeletal muscle or the adipose tissue. It is now clear that a single session of exercise is accompanied by the production of liver-secreted proteins. Hepatokines can also mediate the beneficial effects of chronic exercise or, at least, represent biomarkers of training-induced metabolic improvements. (https://journals.physiology.org/doi/full/10.1152/ajpendo.00433.2018) hepatokines directly affect the progression of atherosclerosis by modulating endothelial dysfunction and infiltration of inflammatory cells into vessel walls. (https://e-dmj.org/journal/view.php?doi=10.4093/dmj.2015.39.1.10)

Types of Hepatokines

(https://link.springer.com/article/10.1007/s00125-015-3634-4)

• Fetuin-A was the first hepatokine to be described and correlated with increased inflammation and insulin resistance
• Fetuin-B significantly increases hepatic steatosis and mediates impaired insulin action and glucose intolerance (https://e-century.us/files/ajtr/15/2/ajtr0142870.pdf)

• ANGPTL8/betatrophin, initially proposed for its action on beta cell proliferation, although this effect has recently been brought into question
• FGF-21 an insulin-sensitising hormone that is an appealing drug target because of its beneficial metabolic actions.

• Adropin is linked to macronutrient intake. (https://hal.science/hal-02402566v1/preview/hepatokines diabetes and metabolism final.pdf)
• ANGPTL4 can inhibit lipoprotein lipase and activate cAMP-stimulated lipolysis in adipocytes (https://www.mdpi.com/2072-6643/15/8/1838)

Biological Research

Hepatokines as biomarkers and therapeutic approaches for metabolic diseases. The liver plays a central role in orchestrating whole body energy metabolism through the secretion of hepatokine(s) in response to stress signals (insulin resistance, type 2 diabetes, NASH). Combining proteomic techniques and bioinformatics software platforms may identify variations in pathogenic or beneficial hepatokine(s) (lines a and b) as potential biomarkers for the progression of diseases such as type 2 diabetes and/or NASH. Ideally, hepatokine discovery would also lead to the development of therapeutics to control energy homeostasis, insulin sensitivity and glucose uptake in peripheral tissues, while reducing resistance and inflammation in target tissues.

(https://link.springer.com/article/10.1007/s00125-015-3634-4)

Exercise-induced hepatokines plays a role in regulating energy balance by improving insulin sensitivity, inflammation, and mitochondrial function, thereby contributing to the improvement of metabolic disorders. Exercise-induced hepatokines might also create a paradigm shift in strategies to diagnose and treat chronic metabolic diseases. Collectively, the benefits of exercise-induced hepatokines have revealed changes to the adipose tissue, vessel, and skeletal muscle for metabolic function. https://www.mdpi.com/2077-0383/10/3/385

although substantial progress has been made in understanding disease-controlled production of hepatokines, little is known about the inductive mechanism of transcriptional reprogramming, protein translation, modification, and secretion of hepatokines, particularly through the ER and Golgi, by pathological processes; (2) feedback signaling from distant organs that are induced by hepatokines and the reciprocation between hepatokines and other 'organokines' are poorly recognized. Several proteins (e.g. FGF21 and soluble epidermal growth factor receptor) can be secreted from the liver and other organs, which act as hepatokine, adipokine, and/or myokine under different circumstances 168, 169. How these signals are spatio-temporally regulated to maintain functional interorgan communication is largely unknown, which needs cutting-edge techniques, such as specific cell type-transgenic method and single-cell sequencing, to answer; (3) whether different liver diseases (e.g., viral hepatitis and metabolic liver diseases) share similar hepatokine secretion profiles needs further investigation. That is, from a translational perspective, searching a single or set of hepatokines as biomarkers for certain diseases is critical for clinical applications. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847667/

The identification and functional characterization of hepatokines may provide significant insights that could help in better understanding of MetS pathogenesis. (https://www.sciencedirect.com/science/article/abs/pii/S1871402119303637?casa_token=DUrzYNVgwlEAAAAA:C5haAz5stBlR_55G87MePEn3hY8aWNpDwCuhJ7-F5z8ubDn-jEztvOdTU7ZKEgjGCwARAb-yPE8) A study was done and concluded that pomegranate extract is effective in improving serum levels of hepatokines. https://www.sciencedirect.com/science/article/abs/pii/S1871402122003101?casa_token=V71wnAGsCxAAAAAA:z9fs5WSIUvvSMeMQcGSIwkuHQP2NoUkT9rVOWIX_PoSb69giwfb6Vj6HkP3duBA4iQNJcyt5fXY The dysregulation of hepatokines is frequently accompanied by changes in bone mass, and osteokines can also disrupt liver metabolism. The crosstalk between the liver and bone, particularly the function and mechanism of hepatokines and osteokines, has increasingly gained notoriety as a topic of interest in recent years (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10117885/) There are potential roles of hepatokines as a class of hormones that substantially influence nutritional regulation in both females and males. (https://hal.science/hal-02402566v1/preview/hepatokines diabetes and metabolism final.pdf)

References

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