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'''Hepatokines''' (Greek ''heapto-'', liver; and ''-kinos'', movement) are [[protein]]s produced by [[liver]] cells ([[hepatocyte]]s) that are [[Secretion|secreted]] into the [[Circulatory system|circulation]] and function as [[hormone]]s 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 disease|fatty liver]] and include: [[Adropin]], [[ANGPTL4]], [[Fetuin-A]], [[Fetuin-B]], [[FGF21|FGF-21]], [[Hepassocin]], [[LECT2]], [[Retinol binding protein 4|RBP4]],[[Selenoprotein P]], [[Sex hormone-binding globulin]].<ref>{{Cite journal |last1=Meex |first1=Ruth C. R. |last2=Watt |first2=Matthew J. |date=September 2017 |title=Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance |url=https://www.nature.com/articles/nrendo.2017.56 |journal=Nature Reviews Endocrinology |language=en |volume=13 |issue=9 |pages=509–520 |doi=10.1038/nrendo.2017.56 |pmid=28621339 |s2cid=302689 |issn=1759-5037}}</ref>
'''Hepatokines''' (Greek ''heapto-'', liver; and ''-kinos'', movement) are [[protein]]s produced by [[liver]] cells ([[hepatocyte]]s) that are [[Secretion|secreted]] into the [[Circulatory system|circulation]] and function as [[hormone]]s 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 disease|fatty liver]] and include: [[Adropin]], [[ANGPTL4]], [[Fetuin-A]], [[Fetuin-B]], [[FGF21|FGF-21]], [[Hepassocin]], [[LECT2]], [[Retinol binding protein 4|RBP4]],[[Selenoprotein P]], [[Sex hormone-binding globulin]].<ref name = "Meex_2017">{{cite journal | vauthors = Meex RC, Watt MJ | title = Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance | journal = Nature Reviews. Endocrinology | volume = 13 | issue = 9 | pages = 509–520 | date = September 2017 | pmid = 28621339 | doi = 10.1038/nrendo.2017.56 | s2cid = 302689 }}</ref>


== General Information ==
== 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.<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 name = "Meex_2017" /> 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 name = "Jensen-Cody_2021">{{cite journal | vauthors = Jensen-Cody SO, Potthoff MJ | title = Hepatokines and metabolism: Deciphering communication from the liver | journal = Molecular Metabolism | volume = 44 | pages = 101138 | date = February 2021 | pmid = 33285302 | doi = 10.1016/j.molmet.2020.101138 | pmc = 7788242 }}</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.
</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>


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 name = "Jensen-Cody_2021" /> Hepatokines signal energy status and help regulate nutrient availability to multiple peripheral tissues and the central nervous system (CNS).<ref name = "Jensen-Cody_2021" /> 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>{{cite journal | vauthors = Ennequin G, Sirvent P, Whitham M | title = Role of exercise-induced hepatokines in metabolic disorders | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 317 | issue = 1 | pages = E11–E24 | date = July 2019 | pmid = 30964704 | doi = 10.1152/ajpendo.00433.2018 | s2cid = 106409704 | url = http://pure-oai.bham.ac.uk/ws/files/68944742/119967_2_merged_1553692814.pdf }}</ref> Hepatokines directly affect the progression of atherosclerosis by modulating endothelial dysfunction and infiltration of inflammatory cells into vessel walls.<ref>{{cite journal | vauthors = Yoo HJ, Choi KM | title = Hepatokines as a Link between Obesity and Cardiovascular Diseases | journal = Diabetes & Metabolism Journal | volume = 39 | issue = 1 | pages = 10–15 | date = February 2015 | pmid = 25729707 | doi = 10.4093/dmj.2015.39.1.10 | pmc = 4342531 }}</ref>
⚫
== Types of Hepatokines ==
[[File:Feutin_A.jpg|thumb|'''(A)''' Fetuin-A structure. '''(B)''' Fetuin-A biosynthesis.]]


⚫
== Types ==
* [[Fetuin-A]] was the first hepatokine to be described and correlated with increased inflammation and insulin resistance <ref>Iroz, Alison, et al. “Hepatokines: Unlocking the Multi-Organ Network in Metabolic Diseases.” ''Diabetologia'', vol. 58, no. 8, 2 June 2015, pp. 1699–1703, <nowiki>https://doi.org/10.1007/s00125-015-3634-4</nowiki>. Accessed 30 Aug. 2021.</ref>
* [[Fetuin-A]] was the first hepatokine to be described and correlated with increased inflammation and insulin resistance.<ref name = "Iroz_2015">{{cite journal | vauthors = Iroz A, Couty JP, Postic C | title = Hepatokines: unlocking the multi-organ network in metabolic diseases | journal = Diabetologia | volume = 58 | issue = 8 | pages = 1699–1703 | date = August 2015 | pmid = 26032022 | doi = 10.1007/s00125-015-3634-4 | s2cid = 7141228 | doi-access = free }}</ref>
* [[Fetuin-B]] significantly increases hepatic steatosis and mediates impaired insulin action and glucose intolerance <ref>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.</ref>
* [[Fetuin-B]] significantly increases hepatic steatosis and mediates impaired insulin action and glucose intolerance.<ref name="Yakout_2023">{{cite journal | vauthors = Yakout SM, Hussein S, Al-Attas OS, Hussain SD, Saadawy GM, Al-Daghri NM | title = Hepatokines fetuin A and fetuin B status in women with/without gestational diabetes mellitus | journal = American Journal of Translational Research | volume = 15 | issue = 2 | pages = 1291–1299 | date = 2023 | pmid = 36915725 | pmc = 10006815 | doi = | url = }}</ref>
* [[ANGPTL8]]/betatrophin, initially proposed for its action on beta cell proliferation, although this effect has recently been brought into question.<ref name = "Iroz_2015" />
* [[FGF21|FGF-21]] an insulin-sensitising hormone that is an appealing drug target because of its beneficial metabolic actions.<ref name = "Iroz_2015" />
* [[Adropin]] is linked to macronutrient intake and estrogen.<ref name = "Smati_2020">{{cite journal | vauthors = Smati S, Régnier M, Fougeray T, Polizzi A, Fougerat A, Lasserre F, Lukowicz C, Tramunt B, Guillaume M, Burnol AF, Postic C, Wahli W, Montagner A, Gourdy P, Guillou H | display-authors = 6 | title = Regulation of hepatokine gene expression in response to fasting and feeding: Influence of PPAR-α and insulin-dependent signalling in hepatocytes | journal = Diabetes & Metabolism | volume = 46 | issue = 2 | pages = 129–136 | date = April 2020 | pmid = 31163275 | doi = 10.1016/j.diabet.2019.05.005 | s2cid = 174810284 | url = https://hal.archives-ouvertes.fr/hal-02402566/file/hepatokines%20diabetes%20and%20metabolism%20final.pdf }}</ref><ref>{{cite journal | vauthors = Stokar J, Gurt I, Cohen-Kfir E, Yakubovsky O, Hallak N, Benyamini H, Lishinsky N, Offir N, Tam J, Dresner-Pollak R | display-authors = 6 | title = Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice | journal = Molecular Metabolism | volume = 60 | pages = 101482 | date = June 2022 | pmid = 35364299 | pmc = 9044006 | doi = 10.1016/j.molmet.2022.101482 }}</ref>
⚫
* [[ANGPTL4]] can inhibit lipoprotein lipase and activate cAMP-stimulated lipolysis in adipocytes.<ref>{{cite journal | vauthors = Zhang Y, Zhu Z, Sun L, Yin W, Liang Y, Chen H, Bi Y, Zhai W, Yin Y, Zhang W | title = Hepatic G Protein-Coupled Receptor 180 Deficiency Ameliorates High Fat Diet-Induced Lipid Accumulation via the Gi-PKA-SREBP Pathway | journal = Nutrients | date = April 2023 | volume = 15 | issue =8 | pages = 1838 | doi = 10.3390/nu15081838 | pmid = 37111058 | pmc = 10144310 | doi-access = free }}</ref>


== Clinical significance ==
* [[ANGPTL8]]/betatrophin, initially proposed for its action on beta cell proliferation, although this effect has recently been brought into question <ref>Iroz, Alison, et al. “Hepatokines: Unlocking the Multi-Organ Network in Metabolic Diseases.” ''Diabetologia'', vol. 58, no. 8, 2 June 2015, pp. 1699–1703, <nowiki>https://doi.org/10.1007/s00125-015-3634-4</nowiki>. Accessed 30 Aug. 2021.</ref>
* [[FGF21|FGF-21]] an insulin-sensitising hormone that is an appealing drug target because of its beneficial metabolic actions. <ref>Iroz, Alison, et al. “Hepatokines: Unlocking the Multi-Organ Network in Metabolic Diseases.” ''Diabetologia'', vol. 58, no. 8, 2 June 2015, pp. 1699–1703, <nowiki>https://doi.org/10.1007/s00125-015-3634-4</nowiki>. Accessed 30 Aug. 2021.</ref>


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.<ref name = "Iroz_2015" />
* [[Adropin]] is linked to macronutrient intake.<ref>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, <nowiki>https://doi.org/10.1016/j.diabet.2019.05.005</nowiki>. Accessed 1 Nov. 2022.</ref>
⚫
* [[ANGPTL4]] can inhibit lipoprotein lipase and activate cAMP-stimulated lipolysis in adipocytes <ref>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, <nowiki>https://doi.org/10.3390/nu15081838</nowiki>. Accessed 26 Apr. 2023.</ref>


Secreted hepatokines in response to exercise induce favorable metabolic changes in fat, blood vessles, and skeletal muscle that can reduce metabolic diseases.<ref>{{cite journal | vauthors = Seo DY, Park SH, Marquez J, Kwak HB, Kim TN, Bae JH, Koh JH, Han J | display-authors = 6 | title = Hepatokines as a Molecular Transducer of Exercise | journal = Journal of Clinical Medicine | volume = 10 | issue = 3 | date = January 2021 | page = 385 | pmid = 33498410 | doi = 10.3390/jcm10030385 | pmc = 7864203 | doi-access = free }}</ref>
== 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."<ref>Iroz, Alison, et al. “Hepatokines: Unlocking the Multi-Organ Network in Metabolic Diseases.” ''Diabetologia'', vol. 58, no. 8, 2 June 2015, pp. 1699–1703, <nowiki>https://doi.org/10.1007/s00125-015-3634-4</nowiki>. Accessed 30 Aug. 2021.</ref>


⚫
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.<ref name = "Wang_2021" /> The identification and functional characterization of hepatokines may provide significant insights that could help in better understanding of MetS pathogenesis.<ref>{{cite journal | vauthors = Esfahani M, Baranchi M, Goodarzi MT | title = The implication of hepatokines in metabolic syndrome | journal = Diabetes & Metabolic Syndrome | year = 2019 | volume = 13 | issue = 4 | pages = 2477–2480 | pmid = 31405664 | doi = 10.1016/j.dsx.2019.06.027 | s2cid = 198296158 }}</ref>
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."<ref>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, <nowiki>https://doi.org/10.3390/jcm10030385</nowiki>. Accessed 30 Mar. 2022.</ref>


=== Non-alcoholic fatty liver disease ===
⚫
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. <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.</ref> The identification and functional characterization of hepatokines may provide significant insights that could help in better understanding of MetS pathogenesis.<ref>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, <nowiki>https://doi.org/10.1016/j.dsx.2019.06.027</nowiki>. Accessed 27 Sept. 2020.</ref>


Hepatokines, sometimes referred to as hepatocytes-derived cytokines<ref>{{cite journal | vauthors = Lu Y, Zheng MH, Wang H | title = Are hepatocytes endocrine cells? | journal = Metabolism and Target Organ Damage | date = March 2023 | volume = 3 | issue = 1 | page = 3 | doi = 10.20517/mtod.2023.11 | s2cid = 257890679 | doi-access = free }}</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>{{cite journal | vauthors = Kim TH, Hong DG, Yang YM | title = Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism | journal = Biomedicines | volume = 9 | issue = 12 | date = December 2021 | page = 1903 | pmid = 34944728 | doi = 10.3390/biomedicines9121903 | pmc = 8698516 | doi-access = free }}</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 name = "Wang_2021">{{cite journal | vauthors = Wang F, So KF, Xiao J, Wang H | title = Organ-organ communication: The liver's perspective | date = January 2021 | journal = Theranostics | volume = 11 | issue = 7 | pages = 3317–3330 | pmid = 33537089 | doi = 10.7150/thno.55795 | pmc = 7847667 }}</ref> 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.<ref name="pmid28025491">{{cite journal | vauthors = Oh KJ, Lee DS, Kim WK, Han BS, Lee SC, Bae KH | title = Metabolic Adaptation in Obesity and Type II Diabetes: Myokines, Adipokines and Hepatokines | journal = International Journal of Molecular Sciences | volume = 18 | issue = 1 | date = December 2016 | page = 8 | pmid = 28025491 | pmc = 5297643 | doi = 10.3390/ijms18010008 | doi-access = free }}</ref>
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, <nowiki>https://doi.org/10.1016/j.dsx.2022.102693</nowiki>. 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 years<sup>8</sup> There are potential roles of hepatokines as a class of hormones that substantially influence nutritional regulation in both females and males.<ref>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, <nowiki>https://doi.org/10.1016/j.diabet.2019.05.005</nowiki>. Accessed 1 Nov. 2022.</ref>


== Metabolic Diseases ==
==References==
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.<ref name="pmid30964704">{{cite journal | vauthors = Ennequin G, Sirvent P, Whitham M | title = Role of exercise-induced hepatokines in metabolic disorders | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 317 | issue = 1 | pages = E11–E24 | date = July 2019 | pmid = 30964704 | doi = 10.1152/ajpendo.00433.2018 | s2cid = 106409704 | url = http://pure-oai.bham.ac.uk/ws/files/68944742/119967_2_merged_1553692814.pdf }}</ref> 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. <ref name="pmid30964704">{{cite journal | vauthors = Ennequin G, Sirvent P, Whitham M | title = Role of exercise-induced hepatokines in metabolic disorders | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 317 | issue = 1 | pages = E11–E24 | date = July 2019 | pmid = 30964704 | doi = 10.1152/ajpendo.00433.2018 | s2cid = 106409704 | url = http://pure-oai.bham.ac.uk/ws/files/68944742/119967_2_merged_1553692814.pdf }}</ref> Hepatokines are now considered potential targets for the treatment of cardiometabolic disorders.<ref name="pmid27051596">{{cite journal | vauthors = Jung TW, Yoo HJ, Choi KM | title = Implication of hepatokines in metabolic disorders and cardiovascular diseases | journal = BBA Clinical | volume = 5 | issue = | pages = 108–13 | date = June 2016 | pmid = 27051596 | pmc = 4816030 | doi = 10.1016/j.bbacli.2016.03.002 }}</ref>

#
# ^ 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, <nowiki>https://doi.org/10.1016/j.dsx.2019.06.027</nowiki>. Accessed 27 Sept. 2020.
# ^ 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.
# ^ 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.
# ^ Iroz, Alison, et al. “Hepatokines: Unlocking the Multi-Organ Network in Metabolic Diseases.” ''Diabetologia'', vol. 58, no. 8, 2 June 2015, pp. 1699–1703, <nowiki>https://doi.org/10.1007/s00125-015-3634-4</nowiki>. Accessed 30 Aug. 2021.
# ^ 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, <nowiki>https://doi.org/10.1016/j.dsx.2022.102693</nowiki>. Accessed 10 Jan. 2023.
# ^ 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.
# ^ 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.
# ^ Li, Zhanghao, et al. “The Roles of Hepatokine and Osteokine in Liver-Bone Crosstalk: Advance in Basic and Clinical Aspects.” ''Frontiers in Endocrinology'', vol. 14, 6 Apr. 2023, www.ncbi.nlm.nih.gov/pmc/articles/PMC10117885/, <nowiki>https://doi.org/10.3389/fendo.2023.1149233</nowiki>. Accessed 26 Apr. 2023.
# ^ 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.
# ^ 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, <nowiki>https://doi.org/10.1038/nrendo.2017.56</nowiki>. Accessed 5 Dec. 2020.
# ^ 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, <nowiki>https://doi.org/10.3390/jcm10030385</nowiki>. Accessed 30 Mar. 2022.
# ^ 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, <nowiki>https://doi.org/10.1016/j.diabet.2019.05.005</nowiki>. Accessed 1 Nov. 2022.
# ^ 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.
# ^ 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.
# ^ 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, <nowiki>https://doi.org/10.3390/nu15081838</nowiki>. Accessed 26 Apr. 2023.


== See also ==
== See also ==

* [[Adipokine]]s
* [[Adipokine]]s
* [[Myokine]]s
* [[Myokine]]s


==References==
== References ==
{{Reflist}}
{{Reflist}}


Line 56: Line 39:
[[Category:Liver]]
[[Category:Liver]]
[[Category:Peptide hormones]]
[[Category:Peptide hormones]]

# ^ 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, <nowiki>https://doi.org/10.1016/j.dsx.2019.06.027</nowiki>. Accessed 27 Sept. 2020.
# ^ 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.
# ^ 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.
# ^ Iroz, Alison, et al. “Hepatokines: Unlocking the Multi-Organ Network in Metabolic Diseases.” ''Diabetologia'', vol. 58, no. 8, 2 June 2015, pp. 1699–1703, <nowiki>https://doi.org/10.1007/s00125-015-3634-4</nowiki>. Accessed 30 Aug. 2021.
# ^ 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, <nowiki>https://doi.org/10.1016/j.dsx.2022.102693</nowiki>. Accessed 10 Jan. 2023.
# ^ 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.
# ^ 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.
# ^ Li, Zhanghao, et al. “The Roles of Hepatokine and Osteokine in Liver-Bone Crosstalk: Advance in Basic and Clinical Aspects.” ''Frontiers in Endocrinology'', vol. 14, 6 Apr. 2023, www.ncbi.nlm.nih.gov/pmc/articles/PMC10117885/, <nowiki>https://doi.org/10.3389/fendo.2023.1149233</nowiki>. Accessed 26 Apr. 2023.
# ^ 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.
# ^ 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, <nowiki>https://doi.org/10.1038/nrendo.2017.56</nowiki>. Accessed 5 Dec. 2020.
# ^ 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, <nowiki>https://doi.org/10.3390/jcm10030385</nowiki>. Accessed 30 Mar. 2022.
# ^ 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, <nowiki>https://doi.org/10.1016/j.diabet.2019.05.005</nowiki>. Accessed 1 Nov. 2022.
# ^ 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.
# ^ 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.
# ^ 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, <nowiki>https://doi.org/10.3390/nu15081838</nowiki>. Accessed 26 Apr. 2023.



{{Protein-stub}}
{{Protein-stub}}

Revision as of 04:09, 31 October 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]

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. ^ a b 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. ^ a b c 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. ^ a b c d 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. PMC 10144310. PMID 37111058.
  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. ^ a b 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): 8. doi:10.3390/ijms18010008. PMC 5297643. PMID 28025491.
  16. ^ a b 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.
  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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