Hepatokine

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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]

Contents

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

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

Related Research Articles

<span class="mw-page-title-main">Metabolic syndrome</span> Medical condition

Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).

Insulin resistance (IR) is a pathological condition in which cells either fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Ketogenesis</span> Chemical synthesis of ketone bodies

Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep, or others.

<span class="mw-page-title-main">Adipose tissue</span> Loose connective tissue composed mostly by adipocytes

Adipose tissue is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

<span class="mw-page-title-main">Insulin-like growth factor 1</span> Protein found in humans

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. In the 1950s IGF-1 was called "sulfation factor" because it stimulated sulfation of cartilage in vitro, and in the 1970s due to its effects it was termed "nonsuppressible insulin-like activity" (NSILA).

<span class="mw-page-title-main">Adiponectin</span> Mammalian protein found in Homo sapiens

Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.

<span class="mw-page-title-main">Fatty liver disease</span> Medical condition related to obesity

Fatty liver disease (FLD), also known as hepatic steatosis and steatotic liver disease (SLD), is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complications may include cirrhosis, liver cancer, and esophageal varices.

In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

<span class="mw-page-title-main">Fetuin</span> Blood proteins made in the liver and secreted into the bloodstream

Fetuins are blood proteins that are made in the liver and secreted into the bloodstream. They belong to a large group of binding proteins mediating the transport and availability of a wide variety of cargo substances in the bloodstream. Fetuin-A is a major carrier protein of free fatty acids in the circulation. The best known representative of carrier proteins is serum albumin, the most abundant protein in the blood plasma of adult animals. Fetuin is more abundant in fetal blood, hence the name "fetuin". Fetal bovine serum contains more fetuin than albumin, while adult serum contains more albumin than fetuin.

Pulsatile intravenous insulin therapy, sometimes called metabolic activation therapy or cellular activation therapy, describes in a literal sense the intravenous injection of insulin in pulses versus continuous infusions. Injection of insulin in pulses mimics the physiological secretions of insulin by the pancreas into the portal vein which then drains into the liver. In healthy, non-diabetic individuals, pancreatic secretions of insulin correspond to the intake of food. The pancreas will secrete variable amounts of insulin based upon the amount of food consumed among other factors. Continuous exposure to insulin and glucagon is known to decrease the hormones' metabolic effectiveness on glucose production in humans due to the body developing an increased tolerance to the hormones. Down-regulation at the cellular level may partially explain the decreased action of steady-state levels of insulin, while pulsatile hormone secretion may allow recovery of receptor affinity and numbers for insulin. Intermittent intravenous insulin administration with peaks of insulin concentrations may enhance suppression of gluconeogenesis and reduce hepatic glucose production.

<span class="mw-page-title-main">Fatty acid-binding protein</span>

The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and intracellular membranes. Some family members are also believed to transport lipophilic molecules from outer cell membrane to certain intracellular receptors such as PPAR. The FABPs are intracellular carriers that “solubilize” the endocannabinoid anandamide (AEA), transporting AEA to the breakdown by FAAH, and compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids are also discovered to bind human FABPs that function as intracellular carriers, as THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. Levels of fatty-acid-binding protein have been shown to decline with ageing in the mouse brain, possibly contributing to age-associated decline in synaptic activity.

<span class="mw-page-title-main">Free fatty acid receptor 3</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 3 protein is a G protein coupled receptor that in humans is encoded by the FFAR3 gene. GPRs reside on cell surfaces, bind specific signaling molecules, and thereby are activated to trigger certain functional responses in their parent cells. FFAR3 is a member of the free fatty acid receptor group of GPRs that includes FFAR1, FFAR2, and FFAR4. All of these FFARs are activated by fatty acids. FFAR3 and FFAR2 are activated by certain short-chain fatty acids (SC-FAs), i.e., fatty acids consisting of 2 to 6 carbon atoms whereas FFFAR1 and FFAR4 are activated by certain fatty acids that are 6 to more than 21 carbon atoms long. Hydroxycarboxylic acid receptor 2 is also activated by a SC-FA that activate FFAR3, i.e., butyric acid.

<span class="mw-page-title-main">LECT2</span> Protein-coding gene in the species Homo sapiens

Leukocyte cell-derived chemotaxin-2 (LECT2) is a protein first described in 1996 as a chemotactic factor for neutrophils, i.e. it stimulated human neutrophils to move directionally in an in vitro assay system. The protein was detected in and purified from cultures of Phytohaemagglutinin-activated human T-cell leukemia SKW-3 cells. Subsequent studies have defined LECT2 as a hepatokine, i.e. a substance made and released into the circulation by liver hepatocyte cells that regulates the function of other cells: it is a hepatocyte-derived, hormone-like, signaling protein.

Pyruvate cycling commonly refers to an intracellular loop of spatial movements and chemical transformations involving pyruvate. Spatial movements occur between mitochondria and cytosol and chemical transformations create various Krebs cycle intermediates. In all variants, pyruvate is imported into the mitochondrion for processing through part of the Krebs cycle. In addition to pyruvate, alpha-ketoglutarate may also be imported. At various points, the intermediate product is exported to the cytosol for additional transformations and then re-imported. Three specific pyruvate cycles are generally considered, each named for the principal molecule exported from the mitochondrion: malate, citrate, and isocitrate. Other variants may exist, such as dissipative or "futile" pyruvate cycles.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

Asprosin is a protein hormone produced by mammals in tissues that stimulates the liver to release glucose into the blood stream. Asprosin is encoded by the gene FBN1 as part of the protein profibrillin and is released from the C-terminus of the latter by specific proteolysis. In the liver, asprosin activates rapid glucose release via a cyclic adenosine monophosphate (cAMP)-dependent pathway.

<span class="mw-page-title-main">Gökhan S. Hotamisligil</span> American geneticist

Gökhan S. Hotamisligil is a Turkish-American physician scientist; James Stevens Simmons Chair of Genetics and Metabolism at Harvard T.H. Chan School of Public Health (HSPH); Director of the Sabri Ülker Center for Metabolic Research and associate member of Harvard-MIT Broad Institute, Harvard Stem Cell Institute and the Joslin Diabetes Center.

<span class="mw-page-title-main">Adropin</span> Peptide hormone

Adropin is a protein encoded by the energy homeostasis-associated gene ENHO in humans and is highly conserved across mammals.

References

  1. 1 2 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. 1 2 3 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. 1 2 3 4 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. 1 2 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. 1 2 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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