miR-188 promotes liver steatosis and insulin resistance via the autophagy pathway

in Journal of Endocrinology
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  • 1 Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China
  • 2 Department of Infectious Diseases, Xiangya Hospital of Central South University, Changsha, Hunan, China

Correspondence should be addressed to L Fu and L Luo: fulei92@126.com or lipingluo1987@gmail.com

*(Y Liu and X Zhou contributed equally to this work)

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Nonalcoholic fatty liver disease (NAFLD) is becoming the most prevalent liver disease worldwide, is characterized by liver steatosis and is often accompanied with other pathological features such as insulin resistance. However, the underlying mechanisms are not fully understood, and specific pharmacological agents need to be developed. Here, we investigated the role of microRNA-188 (miR-188) as a negative regulator in hepatic glucose and lipid metabolism. miR-188 was upregulated in the liver of obese mice. Loss of miR-188 alleviated diet-induced hepatosteatosis and insulin resistance. In contrast, liver-specific overexpression of miR-188 aggravated hepatic steatosis and insulin resistance during high-fat diet feeding. Mechanistically, we found that the negative effects of miR-188 on lipid and glucose metabolism were mediated by the autophagy pathway via targeting autophagy-related gene 12 (Atg12). Furthermore, suppressing miR-188 in the liver of obese mice improved liver steatosis and insulin resistance. Taken together, our findings reveal a new regulatory role of miR-188 in glucose and lipid metabolism through the autophagy pathway, and provide a therapeutic insight for NAFLD.

Supplementary Materials

    • Supplementary Figure 1
    • Table 1. MiR-188 predicted targets.

 

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  • Altshuler-Keylin S, Shinoda K, Hasegawa Y, Ikeda K, Hong H, Kang Q, Yang Y, Perera RM, Debnath J & Kajimura S 2016 Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance. Cell Metabolism 24 402419. (https://doi.org/10.1016/j.cmet.2016.08.002)

    • Search Google Scholar
    • Export Citation
  • Baffy G 2015 MicroRNAs in nonalcoholic fatty liver disease. Journal of Clinical Medicine 4 19771988. (https://doi.org/10.3390/jcm4121953)

    • Search Google Scholar
    • Export Citation
  • Bartel DP 2004 MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116 281297. (https://doi.org/10.1016/s0092-8674(04)00045-5)

    • Search Google Scholar
    • Export Citation
  • Betel D, Koppal A, Agius P, Sander C & Leslie C 2010 Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biology 11 R90. (https://doi.org/10.1186/gb-2010-11-8-r90)

    • Search Google Scholar
    • Export Citation
  • Bezman NA, Chakraborty T, Bender T & Lanier LL 2011 miR-150 regulates the development of NK and iNKT cells. Journal of Experimental Medicine 208 27172731. (https://doi.org/10.1084/jem.20111386)

    • Search Google Scholar
    • Export Citation
  • Birkenfeld AL & Shulman GI 2014 Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 59 713723. (https://doi.org/10.1002/hep.26672)

    • Search Google Scholar
    • Export Citation
  • Codogno P & Meijer AJ 2010 Autophagy: a potential link between obesity and insulin resistance. Cell Metabolism 11 449451. (https://doi.org/10.1016/j.cmet.2010.05.006)

    • Search Google Scholar
    • Export Citation
  • Ebato C, Uchida T, Arakawa M, Komatsu M, Ueno T, Komiya K, Azuma K, Hirose T, Tanaka K, Kominami E, et al. 2008 Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metabolism 8 325332. (https://doi.org/10.1016/j.cmet.2008.08.009)

    • Search Google Scholar
    • Export Citation
  • Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, et al. 2006 miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metabolism 3 8798. (https://doi.org/10.1016/j.cmet.2006.01.005)

    • Search Google Scholar
    • Export Citation
  • Garcia DM, Baek D, Shin C, Bell GW, Grimson A & Bartel DP 2011 Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs. Nature Structural and Molecular Biology 18 11391146. (https://doi.org/10.1038/nsmb.2115)

    • Search Google Scholar
    • Export Citation
  • Gonzalez-Rodriguez A, Mayoral R, Agra N, Valdecantos MP, Pardo V, Miquilena-Colina ME, Vargas-Castrillon J, Lo IO, Corazzari M, Fimia GM, et al. 2014 Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death and Disease 5 e1179. (https://doi.org/10.1038/cddis.2014.162)

    • Search Google Scholar
    • Export Citation
  • Haller M, Hock AK, Giampazolias E, Oberst A, Green DR, Debnath J, Ryan KM, Vousden KH & Tait SW 2014 Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity. Autophagy 10 22692278. (https://doi.org/10.4161/15548627.2014.981914)

    • Search Google Scholar
    • Export Citation
  • Hazlehurst JM, Woods C, Marjot T, Cobbold JF & Tomlinson JW 2016 Non-alcoholic fatty liver disease and diabetes. Metabolism: Clinical and Experimental 65 10961108. (https://doi.org/10.1016/j.metabol.2016.01.001)

    • Search Google Scholar
    • Export Citation
  • Huang Y, Xiao Y, Liu Y, Guo M, Guo Q, Zhou F, Liu T, Su T, Xiao Y & Luo XH 2020 MicroRNA-188 regulates aging-associated metabolic phenotype. Aging Cell 19 e13077. (https://doi.org/10.1111/acel.13077)

    • Search Google Scholar
    • Export Citation
  • Ising C, Gallardo G, Leyns CEG, Wong CH, Jiang H, Stewart F, Koscal LJ, Roh J, Robinson GO, Remolina Serrano J, et al. 2017 AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy. Journal of Experimental Medicine 214 12271238. (https://doi.org/10.1084/jem.20162125)

    • Search Google Scholar
    • Export Citation
  • Kim KM, Han CY, Kim JY, Cho SS, Kim YS, Koo JH, Lee JM, Lim SC, Kang KW, Kim JS, et al. 2018 Galpha12 overexpression induced by miR-16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells. Journal of Hepatology 68 493504. (https://doi.org/10.1016/j.jhep.2017.10.011)

    • Search Google Scholar
    • Export Citation
  • Kunanopparat A, Kimkong I, Palaga T, Tangkijvanich P, Sirichindakul B & Hirankarn N 2016 Increased ATG5-ATG12 in hepatitis B virus-associated hepatocellular carcinoma and their role in apoptosis. World Journal of Gastroenterology 22 83618374. (https://doi.org/10.3748/wjg.v22.i37.8361)

    • Search Google Scholar
    • Export Citation
  • Lavallard VJ & Gual P 2014 Autophagy and non-alcoholic fatty liver disease. BioMed Research International 2014 120179. (https://doi.org/10.1155/2014/120179)

    • Search Google Scholar
    • Export Citation
  • Lee K, Kim JH, Kwon OB, An K, Ryu J, Cho K, Suh YH & Kim HS 2012 An activity-regulated microRNA, miR-188, controls dendritic plasticity and synaptic transmission by downregulating neuropilin-2. Journal of Neuroscience 32 56785687. (https://doi.org/10.1523/JNEUROSCI.6471-11.2012)

    • Search Google Scholar
    • Export Citation
  • Lee K, Kim H, An K, Kwon OB, Park S, Cha JH, Kim MH, Lee Y, Kim JH, Cho K, et al. 2016 Replenishment of microRNA-188-5p restores the synaptic and cognitive deficits in 5XFAD mouse model of Alzheimer’s disease. Scientific Reports 6 34433. (https://doi.org/10.1038/srep34433)

    • Search Google Scholar
    • Export Citation
  • Li H, Xie H, Liu W, Hu R, Huang B, Tan YF, Xu K, Sheng ZF, Zhou HD, Wu XP, et al. 2009 A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. Journal of Clinical Investigation 119 36663677. (https://doi.org/10.1172/JCI39832)

    • Search Google Scholar
    • Export Citation
  • Li WC, Ralphs KL & Tosh D 2010 Isolation and culture of adult mouse hepatocytes. Methods in Molecular Biology 96 633185. (https://doi.org/10.1007/978-1-59745-019-5_13)

    • Search Google Scholar
    • Export Citation
  • Li CJ, Cheng P, Liang MK, Chen YS, Lu Q, Wang JY, Xia ZY, Zhou HD, Cao X, Xie H, et al. 2015 MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation. Journal of Clinical Investigation 125 15091522. (https://doi.org/10.1172/JCI77716)

    • Search Google Scholar
    • Export Citation
  • Li CJ, Xiao Y, Yang M, Su T, Sun X, Guo Q, Huang Y & Luo XH 2018a Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging. Journal of Clinical Investigation 128 52515266. (https://doi.org/10.1172/JCI99044)

    • Search Google Scholar
    • Export Citation
  • Li N, Shi H, Zhang L, Li X, Gao L, Zhang G, Shi Y & Guo S 2018b miR-188 inhibits glioma cell proliferation and cell cycle progression through targeting beta-catenin. Oncology Research 26 785794. (https://doi.org/10.3727/096504017X15127309628257)

    • Search Google Scholar
    • Export Citation
  • Liu HY, Han J, Cao SY, Hong T, Zhuo D, Shi J, Liu Z & Cao W 2009 Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. Journal of Biological Chemistry 284 3148431492. (https://doi.org/10.1074/jbc.M109.033936)

    • Search Google Scholar
    • Export Citation
  • Loyer X, Paradis V, Henique C, Vion AC, Colnot N, Guerin CL, Devue C, On S, Scetbun J, Romain M, et al. 2016 Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARalpha expression. Gut 65 18821894. (https://doi.org/10.1136/gutjnl-2014-308883)

    • Search Google Scholar
    • Export Citation
  • Malhotra R, Warne JP, Salas E, Xu AW & Debnath J 2015 Loss of Atg12, but not Atg5, in pro-opiomelanocortin neurons exacerbates diet-induced obesity. Autophagy 11 145154. (https://doi.org/10.1080/15548627.2014.998917)

    • Search Google Scholar
    • Export Citation
  • Meex RCR & Watt MJ 2017 Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nature Reviews: Endocrinology 13 509520. (https://doi.org/10.1038/nrendo.2017.56)

    • Search Google Scholar
    • Export Citation
  • Min HK, Kapoor A, Fuchs M, Mirshahi F, Zhou H, Maher J, Kellum J, Warnick R, Contos MJ & Sanyal AJ 2012 Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metabolism 15 665674. (https://doi.org/10.1016/j.cmet.2012.04.004)

    • Search Google Scholar
    • Export Citation
  • Mori MA, Raghavan P, Thomou T, Boucher J, Robida-Stubbs S, Macotela Y, Russell SJ, Kirkland JL, Blackwell TK & Kahn CR 2012 Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metabolism 16 336347. (https://doi.org/10.1016/j.cmet.2012.07.017)

    • Search Google Scholar
    • Export Citation
  • Neudecker V, Haneklaus M, Jensen O, Khailova L, Masterson JC, Tye H, Biette K, Jedlicka P, Brodsky KS, Gerich ME, et al. 2017 Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. Journal of Experimental Medicine 214 17371752. (https://doi.org/10.1084/jem.20160462)

    • Search Google Scholar
    • Export Citation
  • Newgard CB 2012 Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metabolism 15 606614. (https://doi.org/10.1016/j.cmet.2012.01.024)

    • Search Google Scholar
    • Export Citation
  • Pasquier B 2016 Autophagy inhibitors. Cellular and Molecular Life Sciences 73 9851001. (https://doi.org/10.1007/s00018-015-2104-y)

  • Saponaro C, Gaggini M & Gastaldelli A 2015 Nonalcoholic fatty liver disease and type 2 diabetes: common pathophysiologic mechanisms. Current Diabetes Reports 15 607. (https://doi.org/10.1007/s11892-015-0607-4)

    • Search Google Scholar
    • Export Citation
  • Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM & Czaja MJ 2009 Autophagy regulates lipid metabolism. Nature 458 11311135. (https://doi.org/10.1038/nature07976)

    • Search Google Scholar
    • Export Citation
  • Su T, Xiao Y, Xiao Y, Guo Q, Li C, Huang Y, Deng Q, Wen J, Zhou F & Luo XH 2019 Bone marrow mesenchymal stem cells-derived exosomal miR-29b-3p regulates aging-associated insulin resistance. ACS Nano 13 24502462. (https://doi.org/10.1021/acsnano.8b09375)

    • Search Google Scholar
    • Export Citation
  • Tanaka S, Hikita H, Tatsumi T, Sakamori R, Nozaki Y, Sakane S, Shiode Y, Nakabori T, Saito Y, Hiramatsu N, et al. 2016 Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology 64 19942014. (https://doi.org/10.1002/hep.28820)

    • Search Google Scholar
    • Export Citation
  • Tao ZH, Wan JL, Zeng LY, Xie L, Sun HC, Qin LX, Wang L, Zhou J, Ren ZG, Li YX, et al. 2013 miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma. Journal of Experimental Medicine 210 789803. (https://doi.org/10.1084/jem.20120153)

    • Search Google Scholar
    • Export Citation
  • Tilg H, Moschen AR & Roden M 2017 NAFLD and diabetes mellitus. Nature Reviews: Gastroenterology and Hepatology 14 3242. (https://doi.org/10.1038/nrgastro.2016.147)

    • Search Google Scholar
    • Export Citation
  • Ueno T & Komatsu M 2017 Autophagy in the liver: functions in health and disease. Nature Reviews: Gastroenterology and Hepatology 14 170184. (https://doi.org/10.1038/nrgastro.2016.185)

    • Search Google Scholar
    • Export Citation
  • Wang K, Liu CY, Zhou LY, Wang JX, Wang M, Zhao B, Zhao WK, Xu SJ, Fan LH, Zhang XJ, et al. 2015 APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p. Nature Communications 6 6779. (https://doi.org/10.1038/ncomms7779)

    • Search Google Scholar
    • Export Citation
  • Xiao F, Yu J, Liu B, Guo Y, Li K, Deng J, Zhang J, Wang C, Chen S, Du Y, et al. 2014 A novel function of microRNA 130a-3p in hepatic insulin sensitivity and liver steatosis. Diabetes 63 26312642. (https://doi.org/10.2337/db13-1689)

    • Search Google Scholar
    • Export Citation
  • Xiao Y, Liu H, Yu J, Zhao Z, Xiao F, Xia T, Wang C, Li K, Deng J, Guo Y, et al. 2016 Activation of ERK1/2 ameliorates liver steatosis in leptin receptor-deficient (db/db) mice via stimulating ATG7-dependent autophagy. Diabetes 65 393405. (https://doi.org/10.2337/db15-1024)

    • Search Google Scholar
    • Export Citation
  • Xiao YZ, Yang M, Xiao Y, Guo Q, Huang Y, Li CJ, Cai D & Luo XH 2020 Reducing hypothalamic stem cell senescence protects against aging-associated physiological decline. Cell Metabolism 31 534.e5548.e5. (https://doi.org/10.1016/j.cmet.2020.01.002)

    • Search Google Scholar
    • Export Citation
  • Yang L, Li P, Fu S, Calay ES & Hotamisligil GS 2010 Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metabolism 11 467478. (https://doi.org/10.1016/j.cmet.2010.04.005)

    • Search Google Scholar
    • Export Citation
  • Yang K, Yu B, Cheng C, Cheng T, Yuan B, Li K, Xiao J, Qiu Z & Zhou Y 2017a Mir505-3p regulates axonal development via inhibiting the autophagy pathway by targeting Atg12. Autophagy 13 16791696. (https://doi.org/10.1080/15548627.2017.1353841)

    • Search Google Scholar
    • Export Citation
  • Yang M, Li CJ, Sun X, Guo Q, Xiao Y, Su T, Tu ML, Peng H, Lu Q, Liu Q, et al. 2017b miR-497 approximately 195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1alpha activity. Nature Communications 8 16003. (https://doi.org/10.1038/ncomms16003)

    • Search Google Scholar
    • Export Citation
  • Yang M, Guo Q, Peng H, Xiao YZ, Xiao Y, Huang Y, Li CJ, Su T, Zhang YL, Lei MX, et al. 2019 Kruppel-like factor 3 inhibition by mutated lncRNA Reg1cp results in human high bone mass syndrome. Journal of Experimental Medicine 216 19441964. (https://doi.org/10.1084/jem.20181554)

    • Search Google Scholar
    • Export Citation
  • Yin H, Pasut A, Soleimani VD, Bentzinger CF, Antoun G, Thorn S, Seale P, Fernando P, van Ijcken W, Grosveld F, et al. 2013 MicroRNA-133 controls brown adipose determination in skeletal muscle satellite cells by targeting Prdm16. Cell Metabolism 17 210224. (https://doi.org/10.1016/j.cmet.2013.01.004)

    • Search Google Scholar
    • Export Citation
  • Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, Qiu Y, Burns L, Afendy A & Nader F 2019 The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. Journal of Hepatology 71 793801. (https://doi.org/10.1016/j.jhep.2019.06.021)

    • Search Google Scholar
    • Export Citation
  • Zhang XF, Yang Y, Yang XY & Tong Q 2018 miR-188-3p upregulation results in the inhibition of macrophage proinflammatory activities and atherosclerosis in ApoE-deficient mice. Thrombosis Research 171 1715517161. (https://doi.org/10.1016/j.thromres.2018.09.043)

    • Search Google Scholar
    • Export Citation
  • Zhang Y, Zhang W, Xu A, Tian Y, Liang C & Wang Z 2019 MicroRNA-188 inhibits proliferation migration and invasion of prostate carcinoma by targeting at MARCKS. American Journal of Translational Research 11 50195028.

    • Search Google Scholar
    • Export Citation
  • Zhao L, Ni X, Zhao L, Zhang Y, Jin D, Yin W, Wang D & Zhang W 2018 MiroRNA-188 acts as tumor suppressor in non-small-cell lung cancer by targeting MAP3K3. Molecular Pharmaceutics 15 16821689. (https://doi.org/10.1021/acs.molpharmaceut.8b00071)

    • Search Google Scholar
    • Export Citation
  • Zhu X, Qiu J, Zhang T, Yang Y, Guo S, Li T, Jiang K, Zahoor A, Deng G & Qiu C 2020 MicroRNA-188-5p promotes apoptosis and inhibits cell proliferation of breast cancer cells via the MAPK signaling pathway by targeting Rap2c. Journal of Cellular Physiology 235 23892402. (https://doi.org/10.1002/jcp.29144)

    • Search Google Scholar
    • Export Citation