Circadian Rhythms of the Liver and Their Sexual Dimorphism: Current State of the Problem
https://doi.org/10.35401/2541-9897-2024-9-2-108-114
Abstract
The rhythmicity of life functioning processes at the cellular, organ, and system levels is one of the fundamental properties of living things. Among the wide range of biorhythms, circadian rhythms are the most important for mammals. In mammals, circadian rhythms coordinate a wide range of physiological processes with constantly changing environmental conditions, primarily with light conditions. Data on the characteristics of the circadian rhythms of the liver (the most important organ for maintaining homeostasis) are limited and sometimes even contradictory. We aim to analyze modern literature investigating the organization of circadian rhythms at the gene, cellular, and organ levels. Over the past decades, it has become known that disruption of the normal circadian rhythm of the liver underlies the development of several pathologies. This article highlights some aspects of the normal circadian rhythm functioning and the role of circadian dysfunction in the occurrence of specific pathologies. We also focus on the little-explored issue of sex differences in the circadian rhythms of the mammalian liver.
About the Authors
D. A. Areshidze
Avtsyn Research Institute of Human Morphology of Petrovsky National Research Center of Surgery Research Institute
Russian Federation
Russian Federation
David А. Areshidze, Cand. Sci. (Biol.), Head of the Cell Pathology Laboratory
ulitsa Tsyurupy 3, Moscow, 117418
L. V. Kakturskiy
Avtsyn Research Institute of Human Morphology of Petrovsky National Research Center of Surgery Research Institute
Russian Federation
Russian Federation
Lev V. Kakturskiy, Dr. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences, Scientific Director of the Avtsyn Research Institute of Human Morphology
Moscow
References
1. Chibisov SM, Rapoport SI, Blagonravov ML, eds. Chronobiology and Chronomedicine. RUDN; 2018. (In Russ.).
2. Walker WH 2nd, Bumgarner JR, Walton JC, et al. Light pollution and cancer. Int J Mol Sci. 2020;21(24):9360. PMID: 33302582. PMCID: PMC7764771. https://doi.org/10.3390/ijms21249360
3. Agadzhanyan NA, Makarova II. Earth magnetic field and human organism. Ekologiya cheloveka. 2005;(9):3–9. (In Russ.).
4. Tatevosyan AS, Bykov IM, Gubareva DA. Metabolic influence on circadian oscillations рH and Eh in urine and saliva. Innovative Medicine of Kuban. 2022;7(4):82–89. (In Russ.). https://doi.org/10.35401/2541-9897-2022-25-4-82-89
5. Zimmet P, Alberti KGMM, Stern N, et al. The circadian syndrome: is the metabolic syndrome and much more!. J Intern Med. 2019;286(2):181–191. PMID: 31081577. PMCID: PMC6851668. https://doi.org/10.1111/joim.12924
6. Michel S, Meijer JH. From clock to functional pacemaker. Eur J Neurosci. 2020;51(1):482–493. PMID: 30793396. PMCID: PMC7027845. https://doi.org/10.1111/ejn.14388
7. Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature. 2002;418(6901):935–941. PMID: 12198538. https://doi.org/10.1038/nature00965
8. Leng Y, Musiek ES, Hu K, et al. Association between circadian rhythms and neurodegenerative diseases. Lancet Neurol. 2019;18(3):307–318. PMID: 30784558. PMCID: PMC6426656. https://doi.org/10.1016/S1474-4422(18)30461-7
9. Kuljis DA, Loh DH, Truong D, et al. Gonadal- and sexchromosome-dependent sex differences in the circadian system. Endocrinology. 2013;154(4):1501–1512. PMID: 23439698. PMCID: PMC3602630. https://doi.org/10.1210/en.2012-1921
10. Berthier A, Johanns M, Zummo FP, Lefebvre P, Staels B. PPARs in liver physiology. Biochim Biophys Acta Mol Basis Dis. 2021;1867(5):166097. PMID: 33524529. https://doi.org/10.1016/j.bbadis.2021.166097
11. Kim P, Oster H, Lehnert H, et al. Coupling the circadian clock to homeostasis: the role of period in timing physiology. Endocr Rev. 2019;40(1):66–95. PMID: 30169559. https://doi.org/10.1210/er.2018-00049
12. Takahashi JS, Hong HK, Ko CH, McDearmon EL. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet. 2008;9(10):764–775. PMID: 18802415. PMCID: PMC3758473. https://doi.org/10.1038/nrg2430
13. Koronowski KB, Kinouchi K, Welz PS, et al. Defining the independence of the liver circadian clock. Cell. 2019;177(6):1448– 1462.e14. PMID: 31150621. PMCID: PMC6813833. https://doi. org/10.1016/j.cell.2019.04.025
14. Li H, Zhang S, Zhang W, et al. Endogenous circadian time genes expressions in the liver of mice under constant darkness. BMC Genomics. 2020;21(1):224. PMID: 32160860. PMCID: PMC7066782. https://doi.org/10.1186/s12864-020-6639-4
15. Flessa CM, Kyrou I, Nasiri-Ansari N, Kaltsas G, Kassi E, Randeva HS. Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD). J Cell Biochem. 2022;123(10):1585–1606. PMID: 35490371. https://doi.org/10.1002/jcb.30247
16. Reinke H, Asher G. Circadian clock control of liver metabolic functions. Gastroenterology. 2016;150(3):574–580. PMID: 26657326. https://doi.org/10.1053/j.gastro.2015.11.043
17. Robles MS, Cox J, Mann M. In-vivo quantitative proteomics reveals a key contribution of post-transcriptional mechanisms to the circadian regulation of liver metabolism. PLoS Genet. 2014;10(1):e1004047. PMID: 24391516. PMCID: PMC3879213. https://doi.org/10.1371/journal.pgen.1004047
18. Sun R, Huang J, Yang N, et al. Purine catabolism shows a dampened circadian rhythmicity in a high-fat diet-induced mouse model of obesity. Molecules. 2019;24(24):4524. PMID: 31835615. PMCID: PMC6943701. https://doi.org/10.3390/molecules24244524
19. Akhtar RA, Reddy AB, Maywood ES, et al. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol. 2002;12(7):540–550. PMID: 11937022. https://doi.org/10.1016/ s0960-9822(02)00759-5
20. Vollmers C, Gill S, DiTacchio L, Pulivarthy SR, Le HD, Panda S. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc Natl Acad Sci U S A. 2009;106(50):21453–21458. PMID: 19940241. PMCID: PMC2795502. https://doi.org/10.1073/pnas.0909591106
21. Wang J, Mauvoisin D, Martin E, et al. Nuclear proteomics uncovers diurnal regulatory landscapes in mouse liver. Cell Metab. 2017;25(1):102–117. PMID: 27818260. PMCID: PMC5241201. https://doi.org/10.1016/j.cmet.2016.10.003
22. Zhang Y, Xi X, Mei Y, et al. High-glucose induces retinal pigment epithelium mitochondrial pathways of apoptosis and inhibits mitophagy by regulating ROS/PINK1/Parkin signal pathway. Biomed Pharmacother. 2019;111:1315–1325. PMID: 30841445. https://doi.org/10.1016/j.biopha.2019.01.034
23. McCommis KS, Butler AA. The importance of keeping time in the liver. Endocrinology. 2021;162(2):bqaa230. PMID: 33320193. PMCID: PMC7799431. https://doi.org/10.1210/endocr/ bqaa230 24. Lamia KA, Storch KF, Weitz CJ. Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci U S A. 2008;105(39):15172–15177. PMID: 18779586. PMCID: PMC2532700. https://doi.org/10.1073/pnas.0806717105
24. Rudic RD, McNamara P, Curtis AM, et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2004;2(11):e377. PMID: 15523558. PMCID: PMC524471. https://doi.org/10.1371/journal.pbio.0020377
25. Zhang EE, Kay SA. Clocks not winding down: unravelling circadian networks. Nat Rev Mol Cell Biol. 2010;11(11):764–776. PMID: 20966970. https://doi.org/10.1038/nrm2995
26. Lamia KA, Papp SJ, Yu RT, et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature. 2011;480(7378):552–556. PMID: 22170608. PMCID: PMC3245818. https://doi.org/10.1038/nature10700
27. Jeyaraj D, Scheer FA, Ripperger JA, et al. Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab. 2012;15(3):311– 323. PMID: 22405069. PMCID: PMC3299986. https://doi.org/10.1016/j.cmet.2012.01.020
28. Chaix A, Lin T, Le HD, Chang MW, Panda S. Time-restricted feeding prevents obesity and metabolic syndrome in mice lacking a circadian clock. Cell Metab. 2019;29(2):303–319.e4. PMID: 30174302. PMCID: PMC7751278. https://doi.org/10.1016/j.cmet.2018.08.004
29. Adamovich Y, Aviram R, Asher G. The emerging roles of lipids in circadian control. Biochim Biophys Acta. 2015;1851(8):1017– 1025. PMID: 25483623. https://doi.org/10.1016/j.bbalip.2014.11.013
30. Eckel-Mahan K, Sassone-Corsi P. Metabolism and the circadian clock converge. Physiol Rev. 2013;93(1):107–135. PMID: 23303907. PMCID: PMC3781773. https://doi.org/10.1152/physrev.00016.2012
31. Grimaldi B, Bellet MM, Katada S, et al. PER2 controls lipid metabolism by direct regulation of PPARγ. Cell Metab. 2010;12(5):509–520. PMID: 21035761. PMCID: PMC4103168. https://doi.org/10.1016/j.cmet.2010.10.005
32. Le Martelot G, Canella D, Symul L, et al; CycliX Consortium. Genome-wide RNA polymerase II profiles and RNA accumulation reveal kinetics of transcription and associated epigenetic changes during diurnal cycles. PLoS Biol. 2012;10(11):e1001442. PMID: 23209382. PMCID: PMC3507959. https://doi.org/10.1371/journal.pbio.1001442
33. Frazier K, Chang EB. Intersection of the gut microbiome and circadian rhythms in metabolism. Trends Endocrinol Metab. 2020;31(1):25–36. PMID: 31677970. PMCID: PMC7308175. https://doi.org/10.1016/j.tem.2019.08.013
34. Bottalico LN, Weljie AM. Cross-species physiological interactions of endocrine disrupting chemicals with the circadian clock. Gen Comp Endocrinol. 2021;301:113650. PMID: 33166531. PMCID: PMC7993548. https://doi.org/10.1016/j.ygcen.2020.113650
35. Kalko KO. Chronopharmacological Study of the Activity of Hepatoprotective Medicines. Dissertation abstract. National University of Pharmacy; 2017. (In Ukrainian).
36. Mukherji A, Dachraoui M, Baumert TF. Perturbation of the circadian clock and pathogenesis of NAFLD. Metabolism. 2020;111S:154337. PMID: 32795560. PMCID: PMC7613429. https://doi.org/10.1016/j.metabol.2020.154337
37. Avagimyan A, Popov S, Shalnova S. the pathophysiological basis of diabetic cardiomyopathy development. Curr Probl Cardiol. 2022;47(9):101156. PMID: 35192869. https://doi.org/10.1016/j.cpcardiol.2022.101156
38. Avagimyan A, Fogacci F, Pogosova N, et al. Diabetic cardiomyopathy: 2023 update by the International Multidisciplinary Board of Experts. Curr Probl Cardiol. 2024;49(1 Pt A):102052. PMID: 37640176. https://doi.org/10.1016/j.cpcardiol.2023.102052
39. Samuel VT, Shulman GI. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 2018;27(1):22–41. PMID: 28867301. PMCID: PMC5762395. https://doi.org/10.1016/j.cmet.2017.08.002
40. Saran AR, Dave S, Zarrinpar A. Circadian rhythms in the pathogenesis and treatment of fatty liver disease. Gastroenterology. 2020;158(7):1948–1966.e1. PMID: 32061597. PMCID: PMC7279714. https://doi.org/10.1053/j.gastro.2020.01.050
41. Chen P, Han Z, Yang P, Zhu L, Hua Z, Zhang J. Loss of clock gene mPer2 promotes liver fibrosis induced by carbon tetrachloride. Hepatol Res. 2010;40(11):1117–1127. PMID: 20880056. https://doi.org/10.1111/j.1872-034X.2010.00695.x
42. Tahara Y, Shibata S. Circadian rhythms of liver physiology and disease: experimental and clinical evidence. Nat Rev Gastroenterol Hepatol. 2016;13(4):217–226. PMID: 26907879. https://doi.org/10.1038/nrgastro.2016.8
43. Diallo AB, Coiffard B, Leone M, Mezouar S, Mege JL. For whom the clock ticks: clinical chronobiology for infectious diseases. Front Immunol. 2020;11:1457. PMID: 32733482. PMCID: PMC7363845. https://doi.org/10.3389/fimmu.2020.01457
44. Feillet C, van der Horst GT, Levi F, Rand DA, Delaunay F. Coupling between the circadian clock and cell cycle oscillators: implication for healthy cells and malignant growth. Front Neurol. 2015;6:96. PMID: 26029155. PMCID: PMC4426821. https://doi.org/10.3389/fneur.2015.00096
45. Lin YM, Chang JH, Yeh KT, et al. Disturbance of circadian gene expression in hepatocellular carcinoma. Mol Carcinog. 2008;47(12):925–933. PMID: 18444243. https://doi.org/10.1002/mc.20446
46. Yeh CT, Lu SC, Tseng IC, et al. Antisense overexpression of BMAL2 enhances cell proliferation. Oncogene. 2003;22(34):5306– 5314. PMID: 12917632. https://doi.org/10.1038/sj.onc.1206674
47. Cui M, Sun J, Hou J, et al. The suppressor of cytokine signaling 2 (SOCS2) inhibits tumor metastasis in hepatocellular carcinoma. Tumour Biol. 2016;37(10):13521–13531. PMID: 27465557. https://doi.org/10.1007/s13277-016-5215-7
48. Lee JH, Sancar A. Circadian clock disruption improves the efficacy of chemotherapy through p73-mediated apoptosis. Proc Natl Acad Sci U S A. 2011;108(26):10668–10672. PMID: 21628572. PMCID: PMC3127903. https://doi.org/10.1073/pnas.1106284108
49. Kelleher FC, Rao A, Maguire A. Circadian molecular clocks and cancer. Cancer Lett. 2014;342(1):9–18. PMID: 24099911. https://doi.org/10.1016/j.canlet.2013.09.040
50. Filipski E, Subramanian P, Carrière J, Guettier C, Barbason H, Lévi F. Circadian disruption accelerates liver carcinogenesis in mice. Mutat Res. 2009;680(1–2):95–105. PMID: 19833225. https://doi.org/10.1016/j.mrgentox.2009.10.002
51. Jiang Y, Shen X, Fasae MB, et al. The expression and function of circadian rhythm genes in hepatocellular carcinoma. Oxid Med Cell Longev. 2021;2021:4044606. PMID: 34697563. PMCID: PMC8541861. https://doi.org/10.1155/2021/4044606
52. Zhao B, Lu J, Yin J, et al. A functional polymorphism in PER3 gene is associated with prognosis in hepatocellular carcinoma. Liver Int. 2012;32(9):1451–1459. PMID: 22809120. https:// doi.org/10.1111/j.1478-3231.2012.02849.x
53. Kettner NM, Voicu H, Finegold MJ, et al. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell. 2016;30(6):909–924. PMID: 27889186. PMCID: PMC5695235. https://doi.org/10.1016/j.ccell.2016.10.007
54. Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okamura H. Control mechanism of the circadian clock for timing of cell division in vivo. Science. 2003;302(5643):255–259. PMID: 12934012. https://doi.org/10.1126/science.1086271
55. Zou Y, Bao Q, Kumar S, Hu M, Wang GY, Dai G. Four waves of hepatocyte proliferation linked with three waves of hepatic fat accumulation during partial hepatectomy-induced liver regeneration. PLoS One. 2012;7(2):e30675. PMID: 22319576. PMCID: PMC3272022. https://doi.org/10.1371/journal.pone.0030675
56. Chao HW, Doi M, Fustin JM, et al. Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway. Nat Commun. 2017;8(1):2238. PMID: 29269828. PMCID: PMC5740157. https://doi.org/10.1038/s41467-017-02207-7
57. Ozturk N, Ozturk D, Kavakli IH, Okyar A. Molecular aspects of circadian pharmacology and relevance for cancer chronotherapy. Int J Mol Sci. 2017;18(10):2168. PMID: 29039812. PMCID: PMC5666849. https://doi.org/10.3390/ijms18102168
58. Sadiq Z, Varghese E, Büsselberg D. Cisplatin’s dualeffect on the circadian clock triggers proliferation and apoptosis. Neurobiol Sleep Circadian Rhythms. 2020;9:100054. PMID: 33364523. PMCID: PMC7752721. https://doi.org/10.1016/j.nbscr.2020.100054
59. Yang SK, Zhang HR, Shi SP, et al. The role of mitochondria in systemic lupus erythematosus: a glimpse of various pathogenetic mechanisms. Curr Med Chem. 2020;27(20):3346–3361. PMID: 30479205. https://doi.org/10.2174/0929867326666181126165139
60. Llanos JM, Dumm CL, Nessi AC. Ultrastructure of STH cells of the pars distalis of hepatectomized mice. Z Zellforsch Mikrosk Anat. 1971;113(1):29–38. PMID: 5545215. https://doi.org/10.1007/BF00331199
61. Ryzhikov M, Eubanks A, Haspel JA. Measuring diurnal rhythms in autophagic and proteasomal flux. J Vis Exp. 2019;(151):10.3791/60133. PMID: 31609346. https://doi.org/10.3791/60133
62. Fedchenko T, Izmailova O, Shynkevych V, Shlykova O, Kaidashev I. PPAR-γ agonist pioglitazone restored mouse liver mRNA expression of clock genes and inflammation-related genes disrupted by reversed feeding. PPAR Res. 2022;2022:7537210. PMID: 35663475. PMCID: PMC9162826. https://doi.org/10.1155/2022/7537210
63. Sinturel F, Gerber A, Mauvoisin D, et al. Diurnal oscillations in liver mass and cell size accompany ribosome assembly cycles. Cell. 2017;169(4):651–663.e14. PMID: 28475894. PMCID: PMC5570523. https://doi.org/10.1016/j.cell.2017.04.015
64. Weger M, Weger BD, Gachon F. The mechanisms and physiological consequences of diurnal hepatic cell size fluctuations: a brief review. Cell Physiol Biochem. 2022;56(S2):1–11. PMID: 35032423. https://doi.org/10.33594/000000489
65. Shi H, Brown LM, Rahimian R. Sex/gender differences in metabolism and behavior: influence of sex chromosomes and hormones. Int J Endocrinol. 2015;2015:245949. PMID: 26491439. PMCID: PMC4600911. https://doi.org/10.1155/2015/245949
66. Beery AK, Zucker I. Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev. 2011;35(3):565–572. PMID: 20620164. PMCID: PMC3008499. https://doi.org/10.1016/j.neubiorev.2010.07.002
67. Zucker I, Beery AK. Males still dominate animal studies. Nature. 2010;465(7299):690. PMID: 20535186. https://doi.org/10.1038/465690a
68. Marcos RJPC. Age and Gender Influences on the Rat Liver Model: Quantitative Morphological Studies of Hepatic Stellate Cells, Hepatocytes and Kupffer Cells and of Related Functional Parameters. Dissertation. University of Porto; 2013.
69. ShanYS, HsiehYH, SyED, ChiuNT, LinPW. The influence of spleen size on liver regeneration after major hepatectomy in normal and early cirrhotic liver. Liver Int. 2005;25(1):96–100. PMID: 15698405. https://doi.org/10.1111/j.1478-3231.2005.01037.x
70. Klaassen CD, Aleksunes LM. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev. 2010;62(1):1–96. PMID: 20103563. PMCID: PMC2835398. https://doi.org/10.1124/pr.109.002014
71. Justo R, Boada J, Frontera M, Oliver J, Bermúdez J, Gianotti M. Gender dimorphism in rat liver mitochondrial oxidative metabolism and biogenesis. Am J Physiol Cell Physiol. 2005;289(2):C372–C378. PMID: 15800054. https://doi.org/10.1152/ajpcell.00035.2005
72. Lefebvre P, Staels B. Hepatic sexual dimorphism - implications for non-alcoholic fatty liver disease. Nat Rev Endocrinol. 2021;17(11):662–670. PMID: 34417588. https://doi.org/10.1038/s41574-021-00538-6
73. Leskanicova A, Chovancova O, Babincak M, et al. Sexual dimorphism in energy metabolism of Wistar rats using data analysis. Molecules. 2020;25(10):2353. PMID: 32443550. PMCID: PMC7287681. https://doi.org/10.3390/molecules25102353
74. Zheng D, Wang X, Antonson P, Gustafsson JÅ, Li Z. Genomics of sex hormone receptor signaling in hepatic sexual dimorphism. Mol Cell Endocrinol. 2018;471:33–41. PMID: 28554805. PMCID: PMC5702598. https://doi.org/10.1016/j.mce.2017.05.025
75. Bur IM, Cohen-Solal AM, Carmignac D, et al. The circadian clock components CRY1 and CRY2 are necessary to sustain sex dimorphism in mouse liver metabolism. J Biol Chem. 2009;284(14):9066–9073. PMID: 19211562. PMCID: PMC2666555. https://doi.org/10.1074/jbc.M808360200
76. Pinkhasov BB, Selyatinskaya VG, Astrakhantseva EL, Anufrienko EV. Circadian rhythms of carbohydrate metabolism in women with different types of obesity. Bull Exp Biol Med. 2016;161(3):323–326. PMID: 27492405. https://doi.org/10.1007/s10517-016-3406-2
77. Pinkhasov BB, Sorokin MYu, Iankovskaia SV, Mikhaylova NI, Selyatitskaya VG. Gender characteristics of the circadian rhythm of carbohydrate metabolism. Siberian Scientific Medical Journal. 2021;41(2):85–91. (In Russ.). https://doi.org/10.18699/ssmj20210212
78. Soares AF, Paz-Montoya J, Lei H, Moniatte M, Gruetter R. Sexual dimorphism in hepatic lipids is associated with the evolution of metabolic status in mice. NMR Biomed. 2017;30(10):10.1002/nbm.3761. Published correction appears in NMR Biomed. 2017 Dec;30(12). PMID: 28661066. https://doi.org/10.1002/nbm.3761
79. Tucci S, Flögel U, Spiekerkoetter U. Sexual dimorphism of lipid metabolism in very long-chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mice in response to medium-chain triglycerides (MCT). Biochim Biophys Acta. 2015;1852(7):1442–1450. PMID: 25887160. https://doi.org/10.1016/j.bbadis.2015.04.009
80. Guillaumond F, Gréchez-CassiauA, Subramaniam M, et al. Kruppel-like factor KLF10 is a link between the circadian clock and metabolism in liver. Mol Cell Biol. 2010;30(12):3059–3070. PMID: 20385766. PMCID: PMC2876690. https://doi.org/10.1128/MCB.01141-09
81. Pérez-Mendoza M, Rivera-Zavala JB, Rodríguez-Guadarrama AH, et al. Daily cycle in hepatic lipid metabolism in obese mice, Neotomodon alstoni: sex differences. Chronobiol Int. 2018;35(5):643–657. PMID: 29370528. https://doi.org/10.1080/0 7420528.2018.1424178
82. Xu YQ, Zhang D, Jin T, et al. Diurnal variation of hepatic antioxidant gene expression in mice. PLoS One. 2012;7(8):e44237. PMID: 22952936. PMCID: PMC3430632. https://doi.org/10.1371/journal.pone.0044237
Review
For citations:
Areshidze D.A., Kakturskiy L.V. Circadian Rhythms of the Liver and Their Sexual Dimorphism: Current State of the Problem. Innovative Medicine of Kuban. 2024;(2):108-114. https://doi.org/10.35401/2541-9897-2024-9-2-108-114
Views:
772
Email this article 
