MEN1/Menin Regulates the Pathogenesis of Non-Alcoholic Fatty Liver Disease
LI Ran-Ran1,*, XU Zhong-Jin1,*, WANG Sheng-Xuan1, YAN Chuan2, SI Bo2, ZHANG Le-Tian1, ZHANG Xuan1, LIU Ting-Jun1, SHI Ke-Rong1,**
1 College of Animal Science and Technology, Shandong Agricultural University/Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, Tai'an 271018, China; 2 Shandong Xianghe Dairy Co., Ltd., Zaozhuang 277412, China
Abstract：Nonalcoholic fatty liver disease (NAFLD) is a clinical pathological syndrome characterized by hepatic steatosis and lipid storage. It is caused by fatty acid synthesis, oxidation, transport, insulin resistance, oxidative stress, gluconeogenesis and other aspects. It was found that the protein menin encoded by the tumor suppressor gene MEN1 can be widely involved in pathways that regulating the liver metabolism. MEN1/menin was an important regulator of liver metabolism and assumed to be closely associated with the pathogenesis of fatty liver disease. This article generally elucidate the research progress of menin in regulating the lipid metabolism, glucose metabolism, insulin resistance and also inflammation.
[1] 买拉木古丽, 蔡雯, 王淑霞, 等. 2016. 新疆地区维吾尔族非酒精性脂肪肝患者血清脂联素水平及与肝脏酶学指标、血脂的相关性[J]. 中国老年学杂志, 36(12): 2961-2963 .(Mai L M G L, Cai W, Wang S X, et al. 2016. Serum adiponectin level and its correlation with liver enzymes and blood lipids in Uygur patients with nonalcoholic fatty liver disease in Xinjiang[J]. Chinese Journal of Gerontology, 36(12): 2961-2963. [2] 欧阳小予, 陈建平, 杨阳, 等. 2015. 非酒精性脂肪性肝病患者血清 VEGF 水平与 IL-6, hs-CRP 的相关性分析[J]. 医学理论与实践, 28(19): 2589-2590. (Ouyang X Y, Chen J P, Yang Y OuYang X Y, Chen J P, Yang Y, et al.2015. Correlation between serum VEGF level and IL-6, hs-CRP in patients with nonalcoholic fatty liver disease[J]. Medical Theory and Practice, 28(19): 2589-2590. [3] Agarwal S K, Burns A L, Sukhodolets K E, et al.2004. Molecular pathology of the MEN1 gene[J]. Annals of the New York Academy of Sciences, 1014: 189-198. [4] Bitar M S, Ayed A K, Abdel Halim S M, et al.2010. Inflammation and apoptosis in aortic tissues of aged type II diabetes: Amelioration with alpha-lipoic acid through phosphatidylinositol 3-kinase/Akt- dependent mechanism[J]. Life Sciences, 86(23/24): 844-853. [5] Buzzetti E, Pinzani M, Tsochatzis EA, 2016. The multiple-hit pathogenesis of non-alcoholic fatty liver disease(NAFLD)[J]. Metabolism-Clinical and Experimental, 65(8): 1038-1048. [6] Chamberlain J S, 2004. Cachexia in cancer--zeroing in on myosin[J]. The New England Journal of Medicine, 351(20): 2124-2125. [7] Cheng P, Yang S S, Hu X G, et al.2011. Menin prevents liver steatosis through co-activation of peroxisome proliferator-activated receptor alpha[J]. FEBS Letters, 585(21): 3403-3408. [8] Cao Y, Xue Y, Jiang X, et al, 2013. Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation[J]. Journal of Hepatology, 59(6): 1299-1306. [9] Chen G, Wang M, Farley S, et al.2008. Menin promotes the Wnt signaling pathway in pancreatic endocrine cells[J]. Molecular Cancer Research, 6(12): 1894-1907. [10] Day C P, 2011. Non-alcoholic fatty liver disease: A massive problem[J]. Clinical Medicine, 11(2): 176-178. [11] de Andrade G C, Fujise L H, de Santana J E, et al., 2016. Non-alcoholic fatty liver disease (NAFLD) in different populations: A clinical and epidemiological study-sample of São José do Rio Preto[J]. Revista da Associação Médica Brasileira, 62: 218-226. [12] Deng Y, Tang K, Chen R, et al.2018. Effects of Shugan-jianpi recipe on the expression of the p38 MAPK/NF-κB signaling pathway in the hepatocytes of NAFLD rats[J]. Medicines (Basel, Switzerland), 11(2): 176-178. [13] Deusht M, Osak M, NakanO K, et al.2016. Ezetimibe reduced hepatic steatosis induced by dietary oxysterols in nonhuman primates[J]. FEBS Open Bio, 6(10): 1008-1015. [14] Dowman J K, Tomlinson J W, Newsome P N, 2010. Pathogenesis of non-alcoholic fatty liver disease[J]. Monthly Journal of the Association of Physicians, 103(2):71-83. [15] Dreijerink K M, Varoer R A, van Beeqm O, et al.2009. The multiple endocrine neoplasia type 1 (MEN1) tumor suppressor regulates peroxisome proliferator-activated receptor gamma-dependent adipocyte differentiation[J]. Molecular and Cellular Biology, 29(18): 5060-5069. [16] Erbas O, Akseki H S, Aktuq H, et al.2015. Low-grade chronic inflamma-tion induces behavioral stereotypy in rats[J]. Metabolic Brain Disease, 30(3): 739-746. [17] Goto M, Yoshioka T, Battelino T, et al.2001. TNFalpha decreases gluconeogenesis in hepatocytes isolated from 10-day-old rats[J]. Pediatric Research, 49(4): 552-557. [18] Guru S C,Goldsmith P K, Burns A L, et al.1998. Menin, the product of the MEN1 gene, is a nuclear protein[J]. Proceedings of the National Academy of Sciences of the USA, 95(4): 1630-1634. [19] Hughes E, Huang C, 2011. Participation of Akt, menin, and p21 in pregnancy-induced beta-cell proliferation[J]. Endocrinology, 152(3): 847-855. [20] Jun H S, Hwang K, Kim Y, et al.2008. High-fat diet alters PP2A, TC10, and CIP4 expression in visceral adipose tissue of rats[J]. Obesity, 16(6): 1226-1231. [21] Jager R, List B, Knabbe C, et al.2002. Serum levels of the angiogenic factor pleiotrophin in relation to disease stage in lung cancer patients[J]. British Journal of Cancer, 86(6): 858-863. [22] Kanwarp, Pushpjeet, Kowdley, 2016. The metabolic syndrome and its influence on nonalcoholic steatohepatitis[J]. Clinics in Liver Disease, 20(2): 225-243. [23] Karnik S K,Chen H, McLean G W, et al.2007. Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus[J]. Science, 318(5851): 806-809. [24] Kim Y S, Burns A L, Goldsmith P K, et al.1999. Stable overexpression of MEN1 suppresses tumorigenicity of RAS[J]. Oncogene, 18(43): 5936-5942. [25] La P, Desmond A, Hou Z, et al.2006. Tumor suppressor menin: The essential role of nuclear localization signal domains in coordinating gene expression[J]. Oncogene, 25(25): 3537-3546. [26] La P, Schnepp R W, D Pedersen C, et al.2004. Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2[J]. Endocrinology 145(7): 3443-3450. [27] Marchesini G, Brizi M, Morselli-Labate A M, et al.1999. Association of nonalcoholic fatty liver disease with insulin resistance[J]. The American Journal of Medicine, 107(5): 450-455. [28] Mantovani A, Minqolla L, Riqolon O, et al.2016. Nonalcoholic fatty liver disease is independently associated with an in-creased incidence of cardiovascular disease in adult patients with type 1 diabetes[J]. International Journal of Cardiology, 225(10): 387-391. [29] Moller D E, 2001. New drug targets for type 2 diabetes and the metabolic syndrome[J]. Nature, 414(6865): 821-827. [30] Newton K, Dixit V M, 2012. Signaling in innate immunity and inflammation[J]. Cold Spring Harbor Perspectives in Biology, 4(3), DOI: 10.1101/cshperspect.a006049. [31] Naugler W E, Sakurai T, Kim S, et al.2007. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production[J]. Science, 317(5834): 121-124. [32] Poisson A, Zablewska B, Gaudray P, 2003. Menin interacting proteins as clues toward the understanding of multiple endocrine neoplasia type 1[J]. Cancer Letters, 189(1): 1-10. [33] Pahl H L, 1999. Activators and target genes of Rel/NF-kappaB transcription factors[J]. Oncogene, 18(49):6853-6866. [34] Qu S, Altomonte J, Perdomo G, et al.2006. Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism[J]. Endocrinology, 147(12): 5641-5652. [35] Rodgers J T, Vogel R O, Puigserver P, 2011. Clk2 and B56beta mediate insulin-regulated assembly of the PP2A phosphatase holoenzyme complex on Akt[J]. Molecular Cell, 41(4): 471-479. [36] Schnepp R W, Chen Y X, Wang H, et al.2006. Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells[J]. Cancer Research, 66(11):5707-5715. [37] Staehr P, Hother-Nielsen O, Beck-Nielsen H, 2004.The role of the liver in type 2 diabetes[J]. Reviews in Endocrine & Metabolic Disorders, 5(2): 105-110. [38] Song T Y, Lim J, Kim B, et al.2014. The role of tumor suppressor menin in IL-6 regulation in mouse islet tumor cells[J]. Biochemical and Biophysical Research Communications, 451(2): 308-313. [39] Wolfrum C, Asilmaz E, Luca E, et al.2004. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes[J]. Nature, 432(7020): 1027-1032. [40] Wuescher L, Angevine K, Hinds T, et al.2011. Insulin regulates menin expression, cytoplasmic localization, and interaction with FOXO1[J]. American Journal of Physiology Endocrinology and Metabolism, 301(3): E474-483. [41] Wells J M,Esni F, Boivin G P, et al.2007. Wnt/beta-catenin signaling is required for development of the exocrine pancreas[J]. BMC Developmental Biology, 7: 4. [42] Wang Z, Klipfell E, Bennett B J, et al.2011. Gut flora metablism of phosphatidylchoine promotes cardivascular disease[J]. Nature, 472(7341): 57-63. [43] Yang Y, Gurunq B, Wu T, et al.2010. Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene[J]. Proceedings of the National Academy of Sciences of the USA, 107(47): 20358-20363. [44] Zhang H, Li W, Wang Q, et al.2012. Glucose-mediated repression of menin promotes pancreatic beta-cell proliferation[J]. Endocrinology 153(2): 602-611.
