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== General Information ==
== General Information ==
[[File:Hepatic production of secreted factors controls nutrient and energy homeostasis.jpg|thumb|'''Hepatic production of secreted factors controls nutrient and energy homeostasis''']]
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.<ref>Meex, Ruth C. R., and Matthew J. Watt. “Hepatokines: Linking Nonalcoholic Fatty Liver Disease and Insulin Resistance.” Nature Reviews Endocrinology, vol. 13, no. 9, 9 June 2017, pp. 509–520, https://doi.org/10.1038/nrendo.2017.56. Accessed 5 Dec. 2020.
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.<ref>Meex, Ruth C. R., and Matthew J. Watt. “Hepatokines: Linking Nonalcoholic Fatty Liver Disease and Insulin Resistance.” Nature Reviews Endocrinology, vol. 13, no. 9, 9 June 2017, pp. 509–520, https://doi.org/10.1038/nrendo.2017.56. Accessed 5 Dec. 2020.
</ref> 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."<ref>Jensen-Cody, Sharon O., and Matthew J. Potthoff. “Hepatokines and Metabolism: Deciphering Communication from the Liver.” ''Molecular Metabolism'', vol. 44, Feb. 2021, p. 101138, <nowiki>https://doi.org/10.1016/j.molmet.2020.101138</nowiki>. Accessed 4 Apr. 2021.</ref> 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. Hepatokines, sometimes referred to as hepatocytes-derived cytokines<ref>Lu, Yan, et al. “Are Hepatocytes Endocrine Cells?” ''Metabolism and Target Organ Damage'', vol. 3, no. 1, 31 Mar. 2023, p. 3, mtodjournal.net/article/view/5573, <nowiki>https://doi.org/10.20517/mtod.2023.11</nowiki>. Accessed 26 Apr. 2023.</ref> 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.<ref>Kim, Tae Hyun, et al. “Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism.” ''Biomedicines'', vol. 9, no. 12, 14 Dec. 2021, p. 1903, <nowiki>https://doi.org/10.3390/biomedicines9121903</nowiki>. Accessed 6 Sept. 2022.</ref> 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.<ref>Wang, Fei, et al. “Organ-Organ Communication: The Liver’s Perspective.” ''Theranostics'', vol. 11, no. 7, 2021, pp. 3317–3330, <nowiki>https://doi.org/10.7150/thno.55795</nowiki>. Accessed 17 Feb. 2022.p</ref> 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."<ref> Jensen-Cody, Sharon O., and Matthew J. Potthoff. “Hepatokines and Metabolism: Deciphering Communication from the Liver.” ''Molecular Metabolism'', vol. 44, Feb. 2021, p. 101138, <nowiki>https://doi.org/10.1016/j.molmet.2020.101138</nowiki>. Accessed 4 Apr. 2021.</ref> Hepatokines signal energy status and help regulate nutrient availability to multiple peripheral tissues and the central nervous system (CNS).<ref> Jensen-Cody, Sharon O., and Matthew J. Potthoff. “Hepatokines and Metabolism: Deciphering Communication from the Liver.” ''Molecular Metabolism'', vol. 44, Feb. 2021, p. 101138, <nowiki>https://doi.org/10.1016/j.molmet.2020.101138</nowiki>. Accessed 4 Apr. 2021.</ref> 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.<ref>Gaël Ennequin, et al. “Role of Exercise-Induced Hepatokines in Metabolic Disorders.” ''American Journal of Physiology-Endocrinology and Metabolism'', vol. 317, no. 1, 1 July 2019, pp. E11–E24, <nowiki>https://doi.org/10.1152/ajpendo.00433.2018</nowiki>. Accessed 26 Apr. 2023.</ref> Hepatokines directly affect the progression of atherosclerosis by modulating endothelial dysfunction and infiltration of inflammatory cells into vessel walls.<ref>Hye Jin Yoo, and Kyung Cheol Choi. “Hepatokines as a Link between Obesity and Cardiovascular Diseases.” ''Diabetes & Metabolism Journal'', vol. 39, no. 1, 1 Feb. 2015, pp. 10–10, <nowiki>https://doi.org/10.4093/dmj.2015.39.1.10</nowiki>. Accessed 26 Apr. 2023.</ref>
</ref> 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."<ref>Jensen-Cody, Sharon O., and Matthew J. Potthoff. “Hepatokines and Metabolism: Deciphering Communication from the Liver.” ''Molecular Metabolism'', vol. 44, Feb. 2021, p. 101138, <nowiki>https://doi.org/10.1016/j.molmet.2020.101138</nowiki>. Accessed 4 Apr. 2021.</ref> 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. Hepatokines, sometimes referred to as hepatocytes-derived cytokines<ref>Lu, Yan, et al. “Are Hepatocytes Endocrine Cells?” ''Metabolism and Target Organ Damage'', vol. 3, no. 1, 31 Mar. 2023, p. 3, mtodjournal.net/article/view/5573, <nowiki>https://doi.org/10.20517/mtod.2023.11</nowiki>. Accessed 26 Apr. 2023.</ref> 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.<ref>Kim, Tae Hyun, et al. “Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism.” ''Biomedicines'', vol. 9, no. 12, 14 Dec. 2021, p. 1903, <nowiki>https://doi.org/10.3390/biomedicines9121903</nowiki>. Accessed 6 Sept. 2022.</ref> 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.<ref>Wang, Fei, et al. “Organ-Organ Communication: The Liver’s Perspective.” ''Theranostics'', vol. 11, no. 7, 2021, pp. 3317–3330, <nowiki>https://doi.org/10.7150/thno.55795</nowiki>. Accessed 17 Feb. 2022.p</ref> 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."<ref> Jensen-Cody, Sharon O., and Matthew J. Potthoff. “Hepatokines and Metabolism: Deciphering Communication from the Liver.” ''Molecular Metabolism'', vol. 44, Feb. 2021, p. 101138, <nowiki>https://doi.org/10.1016/j.molmet.2020.101138</nowiki>. Accessed 4 Apr. 2021.</ref> Hepatokines signal energy status and help regulate nutrient availability to multiple peripheral tissues and the central nervous system (CNS).<ref> Jensen-Cody, Sharon O., and Matthew J. Potthoff. “Hepatokines and Metabolism: Deciphering Communication from the Liver.” ''Molecular Metabolism'', vol. 44, Feb. 2021, p. 101138, <nowiki>https://doi.org/10.1016/j.molmet.2020.101138</nowiki>. Accessed 4 Apr. 2021.</ref> 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.<ref>Gaël Ennequin, et al. “Role of Exercise-Induced Hepatokines in Metabolic Disorders.” ''American Journal of Physiology-Endocrinology and Metabolism'', vol. 317, no. 1, 1 July 2019, pp. E11–E24, <nowiki>https://doi.org/10.1152/ajpendo.00433.2018</nowiki>. Accessed 26 Apr. 2023.</ref> Hepatokines directly affect the progression of atherosclerosis by modulating endothelial dysfunction and infiltration of inflammatory cells into vessel walls.<ref>Hye Jin Yoo, and Kyung Cheol Choi. “Hepatokines as a Link between Obesity and Cardiovascular Diseases.” ''Diabetes & Metabolism Journal'', vol. 39, no. 1, 1 Feb. 2015, pp. 10–10, <nowiki>https://doi.org/10.4093/dmj.2015.39.1.10</nowiki>. Accessed 26 Apr. 2023.</ref>

Revision as of 04:46, 27 April 2023

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]

General Information

File:Hepatic production of secreted factors controls nutrient and energy homeostasis.jpg
Hepatic production of secreted factors controls nutrient and energy homeostasis

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.[2] 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."[3] 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. Hepatokines, sometimes referred to as hepatocytes-derived cytokines[4] 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.[5] 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.[6] 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."[7] Hepatokines signal energy status and help regulate nutrient availability to multiple peripheral tissues and the central nervous system (CNS).[8] 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.[9] Hepatokines directly affect the progression of atherosclerosis by modulating endothelial dysfunction and infiltration of inflammatory cells into vessel walls.[10]

Types of Hepatokines

File:Feutin A.jpg
(A) Fetuin-A structure. (B) Fetuin-A biosynthesis.
  • Fetuin-A was the first hepatokine to be described and correlated with increased inflammation and insulin resistance [11]
  • Fetuin-B significantly increases hepatic steatosis and mediates impaired insulin action and glucose intolerance [12]
  • ANGPTL8/betatrophin, initially proposed for its action on beta cell proliferation, although this effect has recently been brought into question [13]
  • FGF-21 an insulin-sensitising hormone that is an appealing drug target because of its beneficial metabolic actions. [14]
  • Adropin is linked to macronutrient intake.[15]
  • ANGPTL4 can inhibit lipoprotein lipase and activate cAMP-stimulated lipolysis in adipocytes [16]

Biological Research

A study has shown that, "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 hepatokines 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."[17]

Another study proved that, "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."[18]

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. [19] The identification and functional characterization of hepatokines may provide significant insights that could help in better understanding of MetS pathogenesis.[20]

A study was done and concluded that pomegranate extract is effective in improving serum levels of hepatokines. Jafarirad, Sima, et al. “Effectiveness of the Pomegranate Extract in Improving Hepatokines and Serum Biomarkers of Non-Alcoholic Fatty Liver Disease: A Randomized Double Blind Clinical Trial.” Diabetes & Metabolic Syndrome: Clinical Research & Reviews, vol. 17, no. 1, Jan. 2023, p. 102693, https://doi.org/10.1016/j.dsx.2022.102693. Accessed 10 Jan. 2023. 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 years8 There are potential roles of hepatokines as a class of hormones that substantially influence nutritional regulation in both females and males.[21]

See also

References

  1. ^ Meex, Ruth C. R.; Watt, Matthew J. (September 2017). "Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance". Nature Reviews Endocrinology. 13 (9): 509–520. doi:10.1038/nrendo.2017.56. ISSN 1759-5037. PMID 28621339. S2CID 302689.
  2. ^ Meex, Ruth C. R., and Matthew J. Watt. “Hepatokines: Linking Nonalcoholic Fatty Liver Disease and Insulin Resistance.” Nature Reviews Endocrinology, vol. 13, no. 9, 9 June 2017, pp. 509–520, https://doi.org/10.1038/nrendo.2017.56. Accessed 5 Dec. 2020.
  3. ^ Jensen-Cody, Sharon O., and Matthew J. Potthoff. “Hepatokines and Metabolism: Deciphering Communication from the Liver.” Molecular Metabolism, vol. 44, Feb. 2021, p. 101138, https://doi.org/10.1016/j.molmet.2020.101138. Accessed 4 Apr. 2021.
  4. ^ Lu, Yan, et al. “Are Hepatocytes Endocrine Cells?” Metabolism and Target Organ Damage, vol. 3, no. 1, 31 Mar. 2023, p. 3, mtodjournal.net/article/view/5573, https://doi.org/10.20517/mtod.2023.11. Accessed 26 Apr. 2023.
  5. ^ Kim, Tae Hyun, et al. “Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism.” Biomedicines, vol. 9, no. 12, 14 Dec. 2021, p. 1903, https://doi.org/10.3390/biomedicines9121903. Accessed 6 Sept. 2022.
  6. ^ Wang, Fei, et al. “Organ-Organ Communication: The Liver’s Perspective.” Theranostics, vol. 11, no. 7, 2021, pp. 3317–3330, https://doi.org/10.7150/thno.55795. Accessed 17 Feb. 2022.p
  7. ^ Jensen-Cody, Sharon O., and Matthew J. Potthoff. “Hepatokines and Metabolism: Deciphering Communication from the Liver.” Molecular Metabolism, vol. 44, Feb. 2021, p. 101138, https://doi.org/10.1016/j.molmet.2020.101138. Accessed 4 Apr. 2021.
  8. ^ Jensen-Cody, Sharon O., and Matthew J. Potthoff. “Hepatokines and Metabolism: Deciphering Communication from the Liver.” Molecular Metabolism, vol. 44, Feb. 2021, p. 101138, https://doi.org/10.1016/j.molmet.2020.101138. Accessed 4 Apr. 2021.
  9. ^ Gaël Ennequin, et al. “Role of Exercise-Induced Hepatokines in Metabolic Disorders.” American Journal of Physiology-Endocrinology and Metabolism, vol. 317, no. 1, 1 July 2019, pp. E11–E24, https://doi.org/10.1152/ajpendo.00433.2018. Accessed 26 Apr. 2023.
  10. ^ Hye Jin Yoo, and Kyung Cheol Choi. “Hepatokines as a Link between Obesity and Cardiovascular Diseases.” Diabetes & Metabolism Journal, vol. 39, no. 1, 1 Feb. 2015, pp. 10–10, https://doi.org/10.4093/dmj.2015.39.1.10. Accessed 26 Apr. 2023.
  11. ^ Iroz, Alison, et al. “Hepatokines: Unlocking the Multi-Organ Network in Metabolic Diseases.” Diabetologia, vol. 58, no. 8, 2 June 2015, pp. 1699–1703, https://doi.org/10.1007/s00125-015-3634-4. Accessed 30 Aug. 2021.
  12. ^ Yakout, Sobhy, et al. “Original Article Hepatokines Fetuin a and Fetuin B Status in Women With/without Gestational Diabetes Mellitus.” Am J Transl Res, vol. 15, no. 2, 2023, pp. 1291–1299, e-century.us/files/ajtr/15/2/ajtr0142870.pdf. Accessed 26 Apr. 2023.
  13. ^ Iroz, Alison, et al. “Hepatokines: Unlocking the Multi-Organ Network in Metabolic Diseases.” Diabetologia, vol. 58, no. 8, 2 June 2015, pp. 1699–1703, https://doi.org/10.1007/s00125-015-3634-4. Accessed 30 Aug. 2021.
  14. ^ Iroz, Alison, et al. “Hepatokines: Unlocking the Multi-Organ Network in Metabolic Diseases.” Diabetologia, vol. 58, no. 8, 2 June 2015, pp. 1699–1703, https://doi.org/10.1007/s00125-015-3634-4. Accessed 30 Aug. 2021.
  15. ^ Smati, S., et al. “Regulation of Hepatokine Gene Expression in Response to Fasting and Feeding: Influence of PPAR-α and Insulin-Dependent Signalling in Hepatocytes.” Diabetes & Metabolism, vol. 46, no. 2, 1 Apr. 2020, pp. 129–136, www.sciencedirect.com/science/article/pii/S1262363619300886, https://doi.org/10.1016/j.diabet.2019.05.005. Accessed 1 Nov. 2022.
  16. ^ Zhang, Yunhua, et al. “Hepatic G Protein-Coupled Receptor 180 Deficiency Ameliorates High Fat Diet-Induced Lipid Accumulation via the Gi-PKA-SREBP Pathway.” Nutrients, vol. 15, no. 8, 1 Jan. 2023, p. 1838, www.mdpi.com/2072-6643/15/8/1838, https://doi.org/10.3390/nu15081838. Accessed 26 Apr. 2023.
  17. ^ Iroz, Alison, et al. “Hepatokines: Unlocking the Multi-Organ Network in Metabolic Diseases.” Diabetologia, vol. 58, no. 8, 2 June 2015, pp. 1699–1703, https://doi.org/10.1007/s00125-015-3634-4. Accessed 30 Aug. 2021.
  18. ^ Seo, Dae Yun, et al. “Hepatokines as a Molecular Transducer of Exercise.” Journal of Clinical Medicine, vol. 10, no. 3, 20 Jan. 2021, p. 385, https://doi.org/10.3390/jcm10030385. Accessed 30 Mar. 2022.
  19. ^ Wang, Fei, et al. “Organ-Organ Communication: The Liver’s Perspective.” Theranostics, vol. 11, no. 7, 2021, pp. 3317–3330, https://doi.org/10.7150/thno.55795. Accessed 17 Feb. 2022.
  20. ^ Esfahani, Maryam, et al. “The Implication of Hepatokines in Metabolic Syndrome.” Diabetes & Metabolic Syndrome: Clinical Research & Reviews, vol. 13, no. 4, July 2019, pp. 2477–2480, https://doi.org/10.1016/j.dsx.2019.06.027. Accessed 27 Sept. 2020.
  21. ^ Smati, S., et al. “Regulation of Hepatokine Gene Expression in Response to Fasting and Feeding: Influence of PPAR-α and Insulin-Dependent Signalling in Hepatocytes.” Diabetes & Metabolism, vol. 46, no. 2, 1 Apr. 2020, pp. 129–136, www.sciencedirect.com/science/article/pii/S1262363619300886, https://doi.org/10.1016/j.diabet.2019.05.005. Accessed 1 Nov. 2022.
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