Function of apelin/APJ signal in liver cirrhosis and hepatocellular carcinoma

doi:10.16098/j.issn.0529-1356.2018.01.022

Abstract

Abstract:

Apelin/APJ is a G-protein-coupled receptors signal, which is widespread in human and animal tissues including brain, lung, heart, vessels, gastrointestinal tract and kidney, et al. The system plays a vital role in regulating the physiological activities of the human body by participating in multitudinous cell signaling transduction process. Apelin/APJ function mainly includes the regulation of the cardiovascular system homeostasis, maintaining water and electrolyte balance, promoting pituitary hormone release and regulating biological rhythm, and regulating the immune system as an immunomodulatory factor. However, apelin/APJ function is still unknown. In liver, apelin-APJ signal may promote the development of liver fibrosis, cirrhosis and cancer and may play an inhibitory role in liver regeneration. In this review, we summarise the function of apelin/APJ system in hepatic disease.

Key words: Apelin, APJ, Signal, Liver cirrhosis, Hepatocellular carcinoma, Human

LIN Bo PAN Wei-tong KONG Jing Lü Xin-rui. Function of apelin/APJ signal in liver cirrhosis and hepatocellular carcinoma[J]. Acta Anatomica Sinica, 2018, 49(1): 127-131.

References

［1］O’Dowd BF, Heiber M, Chan A, et al. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11 ［J］. Gene, 1993, 136（1-2）: 355-360.

［2］Tatemoto K, Hosoya M, Habata Y, et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor ［J］. Biochem Biophys Res Commun, 1998, 251（2）: 471-476.

［3］He L, Xu J, Chen L, et al. Apelin/APJ signaling in hypoxia-related diseases ［J］. Clin Chim Acta, 2015, 451（Pt B）: 191-198.

［4］Chaves-Almagro C, Castan-Laurell I, Dray C, et al. Apelin receptors: From signaling to antidiabetic strategy ［J］. Eur J Pharmacol, 2015, 763（Pt B）: 149-159.

［5］Kleinz MJ, Davenport AP. Emerging roles of apelin in biology and medicine ［J］. Pharmacol Ther, 2005, 107（2）: 198-211.

［6］Lee DK, Cheng R, Nguyen T, et al. Characterization of apelin, the ligand for the APJ receptor ［J］. J Neurochem, 2000, 74（1）: 34-41.

［7］Medhurst AD, Jennings CA, Robbins MJ, et al. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin ［J］. J Neurochem, 2003, 84（5）: 1162-1172.

［8］Yokomori H, Oda M, Yoshimura K, et al. Enhanced expressions of apelin on proliferative hepatic arterial capillaries in human cirrhotic liver ［J］. Hepatol Res, 2012, 42（5）: 508-514.

［9］Lim YL, Choi E, Jang YO, et al. Clinical implications of the serum apelin level on portal hypertension and prognosis of liver cirrhosis ［J］. Gut Liver, 2016, 10（1）: 109-116.

［10］Lin ZY, Chuang WL. Hepatocellular carcinoma cells cause different responses in expressions of cancer-promoting genes in different cancer-associated fibroblasts ［J］. Kaohsiung J Med Sci, 2013, 29（6）: 312-318.

［11］Yoshiya S, Shirabe K, Imai D, et al. Blockade of the apelin-APJ system promotes mouse liver regeneration by activating Kupffer cells after partial hepatectomy ［J］. J Gastroenterol, 2015, 50（5）: 573-582.

［12］Ishida J, Hashimoto T, Hashimoto Y, et al. Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo ［J］. J Biol Chem, 2004, 279（25）: 26274-26279.

［13］Szokodi I, Tavi P, Foldes G, et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility ［J］. Circ Res, 2002, 91（5）: 434-440.

［14］Cox CM, D’Agostino SL, Miller MK, et al. Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo ［J］. Dev Biol, 2006, 296（1）: 177-189.

［15］Chun HJ, Ali ZA, Kojima Y, et al. Apelin signaling antagonizes Ang Ⅱ effects in mouse models of atherosclerosis ［J］. J Clin Invest, 2008, 118（10）: 3343-3354.

［16］O’Donnell LA, Agrawal A, Sabnekar P, et al. Apelin, an endogenous neuronal peptide, protects hippocampal neurons against excitotoxic injury ［J］. J Neurochem, 2007, 102（6）: 1905-1917.

［17］Cook DR, Gleichman AJ, Cross SA, et al. NMDA receptor modulation by the neuropeptide apelin: implications for excitotoxic injury ［J］. J Neurochem, 2011, 118（6）: 1113-1123.

［18］Khaksari M, Aboutaleb N, Nasirinezhad F, et al. Apelin-13 protects the brain against ischemic reperfusion injury and cerebral edema in a transient model of focal cerebral ischemia ［J］. J Mol Neurosci, 2012, 48（1）: 201-208.

［19］Cayabyab M, Hinuma S, Farzan M, et al. Apelin, the natural ligand of the orphan seven-transmembrane receptor APJ, inhibits human immunodeficiency virus type 1 entry ［J］. J Virol, 2000, 74（24）: 11972-11976.

［20］Kidoya H, Kunii N, Naito H, et al. The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy ［J］. Oncogene, 2011, 31（27）: 3254-3264.

［21］Wang G, Anini Y, Wei W, et al. Apelin, a new enteric peptide: localization in the gastrointestinal tract, ontogeny, and stimulation of gastric cell proliferation and of cholecystokinin secretion ［J］. Endocrinology, 2004, 145（3）: 1342-1348.

［22］Wattez JS, Ravallec R, Cudennec B, et al. Apelin stimulates both cholecystokinin and glucagon-like peptide 1 secretions in vitro and in vivo in rodents ［J］. Peptides, 2013, 48（5）: 134-136.

［23］Sorhede Winzell M, Magnusson C, Ahren B. The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice ［J］. Regul Pept, 2005, 131（1）: 12-17.

［24］Shin K, Chapman NA, Sarker M, et al. Bioactivity of the putative apelin proprotein expands therepertoire of apelin receptor ligands ［J］. Biochim Biophys Acta, 2017,1861(8):1901-1912.

［25］Rak A, Drwal E, Rame C, et al. Knapczyk-Stwora KExpression of apelin and apelin receptor (APJ) in porcine ovarian follicles and in vitro effect of apelin on steroidogenesis and proliferation through APJ activation and different signaling pathways ［J］.Theriogenology, 2017,96:126-135.

［26] Yuan ZS, Zhou YZ, Liao XB, et al. Apelin attenuates the osteoblastic differentiation of aortic valve interstitial cells via the ERK and PI3-K/Akt pathways ［J］. Amino Acids, 2015, 47 (12):2475-2482.

［27］Daviaud D, Boucher J, Gesta S, et al. TNF alpha up-regulates apelin expression in human and mouse adipose tissue ［J］. FASEB J, 2006, 20 (9):1528-1530.

［28］Melgar-Lesmes P, Casals G, Pauta M, et al. Apelin mediates the induction of profibrogenic genes in human hepatic stellate cells ［J］. Endocrinology, 2010, 151（11）: 5306-5314.

［29］RonkainenV, RonkainenJ, Hanninen L, et al. Hypoxia inducible factor regulates the cardiac expression and secretion of apelin ［J］. FASEB J, 2007, 21 (8):1821-1830.

［30］Lv XR, Zheng B, Li SY, et al. Synthetic retinoid Am80 upregulates apelin expression by promoting interaction of RARα with KLF5 and Sp1 in vascular smooth muscle cells ［J］. Biochem J，2013, 456 (2): 35-46.

［31］Chu J, Zhang H, Huang X, et al. Apelin ameliorates TNF-alpha-induced reduction of glycogen synthesis in the hepatocytes through G protein-coupled receptor APJ ［J］. PLoS One, 2013, 8（2）: e57231.

［32］Jeong K, Oh Y, Kim SJ, et al. Apelin is transcriptionally regulated by ER stress-induced ATF4 expression via a p38 MAPK-dependent pathway ［J］. Apoptosis, 2014, 19（9）: 1399-1410.

［33］Melgar-Lesmes P, Pauta M, Reichenbach V, et al. Hypoxia and proinflammatory factors upregulate apelin receptor expression in human stellate cells and hepatocytes ［J］. Gut, 2011, 60（10）: 1404-1411.

［34］Principe A, Melgar-Lesmes P, Fernandez-Varo G, et al. The hepatic apelin system: a new therapeutic target for liver disease ［J］. Hepatology, 2009, 49（3）: 1193-1201.

［35］Drougard A, Duparc T, Brenachot X, et al. Hypothalamic apelin/reactive oxygen species signaling controls hepatic glucose metabolism in the onset of diabetes ［J］. Antioxid Redox Signal, 2014, 20（4）: 557-573.

［36］Kalafateli M, Triantos C, Tsochatzis E, et al. Adipokines levels are associated with the severity of liver disease in patients with alcoholic cirrhosis ［J］. World J Gastroenterol, 2015, 21（10）: 3020-3029.

［37］Yokomori H, Oda M, Yoshimura K, et al. Overexpression of apelin receptor (APJ/AGTRL1) on hepatic stellate cells and sinusoidal angiogenesis in human cirrhotic liver ［J］. J Gastroenterol, 2011, 46（2）: 222-231.

［38］Chen W, Oue T, Ueno T, et al. Apelin is a marker of the progression of liver fibrosis and portal hypertension in patients with biliary atresia ［J］. Pediatr Surg Int, 2013, 29（1）: 79-85.

［39］Lv D, Li L, Lu Q, et al. PAK1-cofilin phosphorylation mediates human lung adenocarcinoma cells migration induced by apelin-13 ［J］. Clin Exp Pharmacol Physiol, 2016, 43（5）: 569-579.

［40］Picault FX, Chaves-Almagro C, Projetti F, et al. Tumour co-expression of apelin and its receptor is the basis of an autocrine loop involved in the growth of colon adenocarcinomas ［J］. Eur J Cancer, 2014, 50（3）: 663-674.

［41］Altinkaya SO, Nergiz S, Kucuk M, et al. Apelin levels are higher in obese patients with endometrial cancer ［J］. J Obstet Gynaecol Res, 2015, 41（2）: 294-300.

［42］Wan Y, Zeng ZC, Xi M, et al. Dysregulated microRNA-224/apelin axis associated with aggressive progression and poor prognosis in patients with prostate cancer ［J］. Hum Pathol, 2015, 46（2）: 295-303.

［43］Farid RM, Abu-Zeid RM, El-Tawil A. Emerging role of adipokine apelin in hepatic remodelling and initiation of carcinogensis in chronic hepatitis C patients ［J］. Int J Clin Exp Pathol, 2014, 7（5）: 2707-2717.

［44］Liu Q, Hu T, He L, et al. Genetic targeting of sprouting angiogenesis using Apln-CreER ［J］. Nat Commun, 2015, 6: 6020.

［45］Takakura N, Kidoya H. Maturation of blood vessels by haematopoietic stem cells and progenitor cells: involvement of apelin/APJ and angiopoietin/Tie2 interactions in vessel caliber size regulation ［J］. Thromb Haemost, 2009, 101（6）: 999-1005.

［46］Sorli SC, Le Gonidec S, Knibiehler B, et al. Apelin is a potent activator of tumour neoangiogenesis ［J］. Oncogene, 2007, 26（55）: 7692-7699.

［47］Muto J, Shirabe K, Yoshizumi T, et al. The apelin-APJ system induces tumor arteriogenesis in hepatocellular carcinoma ［J］. Anticancer Res, 2014, 34（10）: 5313-5320.

［48］Esposito V, De Falco M, De Luca L, et al. Immunohistochemical study of apelin, the natural ligand of receptor APJ, in a case of AIDS-related cachexia ［J］. In Vivo, 2002, 16（5）: 337-340.

［49］Zou MX, Liu HY, Haraguchi Y, et al. Apelin peptides block the entry of human immunodeficiency virus (HIV) ［J］. Febs Letters, 2000, 473（1）: 15-18.

［50］Horiuchi Y, Fujii T, Kamimura Y, et al. The endogenous, immunologically active peptide apelin inhibits lymphocytic cholinergic activity during immunological responses ［J］. J Neuroimmunol, 2003, 144（1-2）: 46-52.

［51］Papangeli I, Kim J, Maier I, et al.MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation ［J］. Nat Commun, 2016,7:11268.

［52］Zang XY，Geng XF，Zhang ChY, et al. Role of microRNAs in liver regeneration ［J］. Acta Anatomica Sinica, 2017, 48 (2):230-235. (in Chinese)

臧夏炎,耿小芳,张春艳,等. MicroRNA在肝再生中的作用研究进展［J］. 解剖学报, 2017,48(2):230-235.

[1]	HONG Xiao-min LI San-qiang CUI Qin-yi ZHENG Run-yue YANG Meng-li LUO Ren-li LI Qian-hui. Nuclear factor-κB signaling pathway and gender differences in alcoholic liver fibrosis [J]. Acta Anatomica Sinica, 2024, 55(1): 55-61.
[2]	LIU Xiao-li XU Lin WU Ai-xue WEN Cai-yun LI Ru-hua WU An-ting CHEN Dai-qian CHEN Cheng-chun. Analysis of cerebral gray matter structure in multiple sclerosis and neuromyelitis optica [J]. Acta Anatomica Sinica, 2024, 55(1): 17-24.
[3]	BAI He TENG Ye FENG Lei MENG Hai-wei1 TANG Yu-chun LIU Shu-wei. 3D hippocampal segmentation based on spatial and frequency domain features adaptive fusion and inter-class boundary region enhancement [J]. Acta Anatomica Sinica, 2024, 55(1): 73-81.
[4]	YIN Shi-qin YANG Si-yi WANG Rui-han YOU Gui-xuan YANG Ying-qiu ZHANG Lei. Distal tibiofibular syndesmosis fibular notch typing and its clinical significance based on CT [J]. Acta Anatomica Sinica, 2024, 55(1): 82-87.
[5]	YANG Yang SHI Jun LI Kun MA Yuan ZHANG Shao-jie HOU Er-fei WANG Chao-qun CHEN Jie WANG Xing LI Zhi-jun. Finite element analysis of cervical intervertebral discs after removing different ranges of uncinate processes [J]. Acta Anatomica Sinica, 2024, 55(1): 88-97.
[6]	SUN Lei WANG Xing-yu XIE Shui-hua. Risk analysis of re-fracture after percutaneous kyphoplasty in elderly patients with osteoporotic thoracolumbar compression fractures and construction of acolumnar graph prediction model#br# [J]. Acta Anatomica Sinica, 2024, 55(1): 98-104.
[7]	LIU Li-ping ZHU Meng-ni XU Hui . Effect of interleukin-6 on nucleated erythrocytes in lipopolysaccharide induced preeclampsia rats [J]. Acta Anatomica Sinica, 2023, 54(6): 722-729.
[8]	ZHAO Wei-ming LI Xiao YU Guo-ying WANG Gai-ping CHANG Cui-fang . Effect of serine protease inhibitor Kazaltype 1 on the proliferation of hepatocellular carcinoma cell and its mechanism [J]. Acta Anatomica Sinica, 2023, 54(6): 695-702.
[9]	CHEN Zi-xuan SI Li-na SHU Wei-han ZHANG Xin WEI Chen-yang CHENG Lu-yang YANG Song-he QIAO Yue-bing. Mechanism of melatonin regulation of PI3K/Akt/mTOR signaling in hypothalamus delaying the initiation of puberty in female mice mice [J]. Acta Anatomica Sinica, 2023, 54(6): 644-651.
[10]	WU Jun-bo YANG Jie XIAO Feng LI Jin-liang . Effect of microRNA-138 regulation of Wnt pathway on the biological behavior of human glioma cells in vitro [J]. Acta Anatomica Sinica, 2023, 54(6): 682-688.
[11]	LI Xia ZHU Shi-jie TANG Zhong-sheng LUO Ya-fei FAN Rui-juan XIE Gao-yu KOU Yun-fang LU Ying. Mechanism of electroacupuncture regulating the ligand pathway of tyrosine kinase receptor in improving vascular dementia [J]. Acta Anatomica Sinica, 2023, 54(6): 689-694.
[12]	HAN Yi CAI Li FENG Xiao . Risk analysis of bone cement leakage after percutaneous puncture vertebroplasty for osteoporotic spinal compression fractures and construction of a predictive model with column line drawings [J]. Acta Anatomica Sinica, 2023, 54(6): 710-715.
[13]	HE Ke-ke LI Yuan-di WEN Ting-hao ZHU Jie GAO Jie HU Rong HAN Feng SU Min . Erythrocyte membrane-associated protein inhibiting Th17 cell differentiation via IL-6/STAT3/ROR-γt signaling pathway in experimental autoimmune encephalomyelitis mice encephalomyelitis mice [J]. Acta Anatomica Sinica, 2023, 54(5): 538-545.
[14]	DU Da-peng SUN Yu ZHANG Min WANG Han-qin . Shear stress regulateing the phosphorylation of endothelial nitric oxide synthase Ser633 and Ser1177 in human umbilical vein endothelial cells through Pim1/Akt pathway [J]. Acta Anatomica Sinica, 2023, 54(5): 546-552.
[15]	ZHOU Chun-hui XIE Sheng-qiang WANG Jiang-ting LAN Xiao-juan ZHANG Jian-ning ZHAO Hu-lin . Application of multimodal electromagnetic navigation in endoscopic endonasal skull base anatomical measurement of fresh cadavers [J]. Acta Anatomica Sinica, 2023, 54(5): 560-566.