Hepatokine

Hepatokines (Greek heapto-, liver; and -kinos, movement) are proteins produced by liver cells (hepatocytes) that are secreted into the circulation and function as hormones across the organism. Research is mostly focused on hepatokines that play a role in the regulation of metabolic diseases such as diabetes and fatty liver and include: Adropin, ANGPTL4, Fetuin-A, Fetuin-B, FGF-21, Hepassocin, LECT2, RBP4,Selenoprotein P, Sex hormone-binding globulin.[1]

Function

Hepatokines are hormone-like proteins secreted by hepatocytes, and many have been associated with extra-hepatic metabolic regulation. Through processes like autocrinem, paracrinem, and endocrine signaling, hepatokines can influence metabolic processes.[1] It has been stated that, "hepatocytes secrete more than 560 types of hepatokines, many of which regulate metabolic and inflammatory diseases in the liver or at distant organs through circulation delivery."[2] 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.

The liver may emit hepatokines to influence energy homeostasis and inflammation under pressure on the metabolism like long-term starvation or over-nutrition. If the liver is unable to fulfill this process, the corresponding disease develops like fatty liver disease from, "impaired hepatic insulin-sensitizing substance production."[2] Hepatokines signal energy status and help regulate nutrient availability to multiple peripheral tissues and the central nervous system (CNS).[2] 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. 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.[3] Hepatokines directly affect the progression of atherosclerosis by modulating endothelial dysfunction and infiltration of inflammatory cells into vessel walls.[4]

Types
  • Fetuin-A was the first hepatokine to be described and correlated with increased inflammation and insulin resistance.[5]
  • Fetuin-B significantly increases hepatic steatosis and mediates impaired insulin action and glucose intolerance.[6]
  • ANGPTL8/betatrophin, initially proposed for its action on beta cell proliferation, although this effect has recently been brought into question.[5]
  • FGF-21 an insulin-sensitising hormone that is an appealing drug target because of its beneficial metabolic actions.[5]
  • Adropin is linked to macronutrient intake and estrogen.[7][8]
  • ANGPTL4 can inhibit lipoprotein lipase and activate cAMP-stimulated lipolysis in adipocytes.[9]

Clinical significance

Hepatokines can serve as biomarkers and are potential therapeutic targets for metabolic diseases. The liver through execretion of hepatokines regulates the whole bodies metabolism in response to stress signals.[5]

Secreted hepatokines in response to exercise induce favorable metabolic changes in fat, blood vessles, and skeletal muscle that can reduce metabolic diseases.[10]

Although substantial progress has been made in understanding disease-controlled production of hepatokines, there is still so much to discover. There is so much room for discovery. For example, "little is known about the inductive mechanism of transcriptional reprogramming, protein translation, modification, and secretion of hepatokines, particularly through the ER and Golgi, and more.[11] The identification and functional characterization of hepatokines may provide significant insights that could help in better understanding of MetS pathogenesis.[12]

Non-alcoholic fatty liver disease

Hepatokines, sometimes referred to as hepatocytes-derived cytokines[13] have been shown to relate to non-alcoholic fatty liver disease. "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.[14] Not only are they involved with metabolic diseseases but they are also linked to diseases of other organs, such as the heart, muscle, bone, and eyes.[11] Recently, it was reported that hepatokine, a secretory protein released from the liver, could affect muscle and fat metabolic phenotypes in an endocrine-dependent manner.[15]

Metabolic Diseases

Early studies in the area reported that a liver-derived protein, alpha2-HS Glycoprotein, also known as Fetuin-A, can inhibit insulin tyrosine kinase activation and might play a role in the pathogenesis of metabolic disorders.[16] Results suggest that hepatokine production could remodel metabolic homeostasis. This is exemplified by a number of studies revealing that hepatokines play a pivotal role in metabolism and contribute to the development of obesity, insulin resistance, T2D, NAFL, and NASH (109, 149). So far, ~20 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. [16] Hepatokines are now considered potential targets for the treatment of cardiometabolic disorders.[17]

See also

References
  1. Meex RC, Watt MJ (September 2017). "Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance". Nature Reviews. Endocrinology. 13 (9): 509–520. doi:10.1038/nrendo.2017.56. PMID 28621339. S2CID 302689.
  2. Jensen-Cody SO, Potthoff MJ (February 2021). "Hepatokines and metabolism: Deciphering communication from the liver". Molecular Metabolism. 44: 101138. doi:10.1016/j.molmet.2020.101138. PMC 7788242. PMID 33285302.
  3. Ennequin G, Sirvent P, Whitham M (July 2019). "Role of exercise-induced hepatokines in metabolic disorders" (PDF). American Journal of Physiology. Endocrinology and Metabolism. 317 (1): E11–E24. doi:10.1152/ajpendo.00433.2018. PMID 30964704. S2CID 106409704.
  4. Yoo HJ, Choi KM (February 2015). "Hepatokines as a Link between Obesity and Cardiovascular Diseases". Diabetes & Metabolism Journal. 39 (1): 10–15. doi:10.4093/dmj.2015.39.1.10. PMC 4342531. PMID 25729707.
  5. Iroz A, Couty JP, Postic C (August 2015). "Hepatokines: unlocking the multi-organ network in metabolic diseases". Diabetologia. 58 (8): 1699–1703. doi:10.1007/s00125-015-3634-4. PMID 26032022. S2CID 7141228.
  6. Yakout SM, Hussein S, Al-Attas OS, Hussain SD, Saadawy GM, Al-Daghri NM (2023). "Hepatokines fetuin A and fetuin B status in women with/without gestational diabetes mellitus". American Journal of Translational Research. 15 (2): 1291–1299. PMC 10006815. PMID 36915725.
  7. Smati S, Régnier M, Fougeray T, Polizzi A, Fougerat A, Lasserre F, et al. (April 2020). "Regulation of hepatokine gene expression in response to fasting and feeding: Influence of PPAR-α and insulin-dependent signalling in hepatocytes" (PDF). Diabetes & Metabolism. 46 (2): 129–136. doi:10.1016/j.diabet.2019.05.005. PMID 31163275. S2CID 174810284.
  8. Stokar J, Gurt I, Cohen-Kfir E, Yakubovsky O, Hallak N, Benyamini H, et al. (June 2022). "Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice". Molecular Metabolism. 60: 101482. doi:10.1016/j.molmet.2022.101482. PMC 9044006. PMID 35364299.
  9. Zhang Y, Zhu Z, Sun L, Yin W, Liang Y, Chen H, Bi Y, Zhai W, Yin Y, Zhang W (April 2023). "Hepatic G Protein-Coupled Receptor 180 Deficiency Ameliorates High Fat Diet-Induced Lipid Accumulation via the Gi-PKA-SREBP Pathway". Nutrients. 15 (8): 1838. doi:10.3390/nu15081838.
  10. Seo DY, Park SH, Marquez J, Kwak HB, Kim TN, Bae JH, et al. (January 2021). "Hepatokines as a Molecular Transducer of Exercise". Journal of Clinical Medicine. 10 (3): 385. doi:10.3390/jcm10030385. PMC 7864203. PMID 33498410.
  11. Wang F, So KF, Xiao J, Wang H (January 2021). "Organ-organ communication: The liver's perspective". Theranostics. 11 (7): 3317–3330. doi:10.7150/thno.55795. PMC 7847667. PMID 33537089.
  12. Esfahani M, Baranchi M, Goodarzi MT (2019). "The implication of hepatokines in metabolic syndrome". Diabetes & Metabolic Syndrome. 13 (4): 2477–2480. doi:10.1016/j.dsx.2019.06.027. PMID 31405664. S2CID 198296158.
  13. Lu Y, Zheng MH, Wang H (March 2023). "Are hepatocytes endocrine cells?". Metabolism and Target Organ Damage. 3 (1): 3. doi:10.20517/mtod.2023.11. S2CID 257890679.
  14. Kim TH, Hong DG, Yang YM (December 2021). "Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism". Biomedicines. 9 (12): 1903. doi:10.3390/biomedicines9121903. PMC 8698516. PMID 34944728.
  15. Oh KJ, Lee DS, Kim WK, Han BS, Lee SC, Bae KH (December 2016). "Metabolic Adaptation in Obesity and Type II Diabetes: Myokines, Adipokines and Hepatokines". International Journal of Molecular Sciences. 18 (1). doi:10.3390/ijms18010008. PMC 5297643. PMID 28025491.
  16. Ennequin G, Sirvent P, Whitham M (July 2019). "Role of exercise-induced hepatokines in metabolic disorders". American Journal of Physiology. Endocrinology and Metabolism. 317 (1): E11–E24. doi:10.1152/ajpendo.00433.2018. PMID 30964704.
  17. Jung TW, Yoo HJ, Choi KM (June 2016). "Implication of hepatokines in metabolic disorders and cardiovascular diseases". BBA Clinical. 5: 108–13. doi:10.1016/j.bbacli.2016.03.002. PMC 4816030. PMID 27051596.
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