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Innate immune regulatory networks in hepatic lipid metabolism

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Abstract

Hepatic lipid metabolism is closely associated with certain diseases, such as obesity, diabetes, fatty liver, and hepatic fibrosis. Hepatic steatosis results from systemic metabolic dysfunction that occurs via multiple processes. The initial process has been characterized as hepatic lipid accumulation that may be caused by increased liver lipid uptake and de novo lipogenesis or decreased lipid oxidation and lipid export; subsequently, multiple additional factors that trigger inflammation and insulin resistance (IR) aggravate the progression of hepatic steatosis. Emerging evidence indicates that inflammation stands at the crossroads of innate immunity and lipid metabolism and links the initial metabolic stress and subsequent metabolic events in lipid metabolism. Therefore, in this review, we summarize the regulatory role of innate immune signaling molecules in maintaining lipid metabolic homeostasis; these revelations can guide the development of potential therapies for nonalcoholic fatty liver disease (NAFLD).

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References

  1. Koliaki C, Roden M (2013) Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease. Mol Cell Endocrinol 379(1–2):35–42

    Article  CAS  PubMed  Google Scholar 

  2. Lonardo A, Ballestri S, Guaraldi G, Nascimbeni F, Romagnoli D, Zona S, Targher G (2016) Fatty liver is associated with an increased risk of diabetes and cardiovascular disease—evidence from three different disease models: NAFLD, HCV and HIV. World J Gastroenterol 22(44):9674–9693

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, Roverato A, Guaraldi G, Lonardo A (2016) Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol 31(5):936–944

    Article  CAS  PubMed  Google Scholar 

  4. Singh S, Osna NA, Kharbanda KK, Singh S, Osna NA, Kharbanda KK (2017) Treatment options for alcoholic and non-alcoholic fatty liver disease: a review. World J Gastroenterol 23:6549–6570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ganesh S, Rustgi VK (2016) Current pharmacologic therapy for nonalcoholic fatty liver disease. Clin Liver Dis 20(2):351–364

    Article  PubMed  Google Scholar 

  6. Byun JS, Yi HS (2017) Hepatic immune microenvironment in alcoholic and nonalcoholic liver disease. Biomed Res Int 2017:6862439

  7. Cai J, Zhang XJ, Li H (2018) Role of innate immune signaling in non-alcoholic fatty liver disease. Trends Endocrinol Metab 29(10):712–722

    Article  CAS  PubMed  Google Scholar 

  8. Neuschwander-Tetri BA (2010) Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52(2):774–788

    Article  PubMed  CAS  Google Scholar 

  9. Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A (2012) The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol 56(4):952–964

    Article  CAS  PubMed  Google Scholar 

  10. Jones JG (2016) Hepatic glucose and lipid metabolism. Diabetologia 59(6):1098–1103

    Article  CAS  PubMed  Google Scholar 

  11. Bril F, Barb D, Portillo-Sanchez P, Biernacki D, Lomonaco R, Suman A, Weber MH, Budd JT, Lupi ME, Cusi K (2017) Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology 65(4):1132–1144

    Article  CAS  PubMed  Google Scholar 

  12. Yki-Järvinen H (2014) Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2(11):901–910

    Article  PubMed  CAS  Google Scholar 

  13. Sochocka M (2008) Recognition of pathogens by innate immunity. Postepy Hig Med Dosw 62:676–687

    Google Scholar 

  14. Lass-Flörl C, Roilides E, Löffler J, Wilflingseder D, Romani L (2013) Minireview: host defence in invasive aspergillosis. Mycoses 56(4):403–413

    Article  PubMed  CAS  Google Scholar 

  15. Costantini C, Cassatella MA (2011) The defensive alliance between neutrophils and NK cells as a novel arm of innate immunity. J Leukoc Biol 89(2):221–233

    Article  CAS  PubMed  Google Scholar 

  16. Xie GC, Duan ZJ (2012) Signal transduction of innate immunity to virus infection. Bing Du Xue Bao 28(3):303–310

    CAS  PubMed  Google Scholar 

  17. Arthur JS, Ley SC (2013) Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 13(9):679–692

    Article  CAS  PubMed  Google Scholar 

  18. Han J, Kaufman RJ (2016) The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res 57(8):1329–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM, Sanyal AJ (2008) Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134(2):568–576

    Article  CAS  PubMed  Google Scholar 

  20. Szabo G, Petrasek J (2015) Inflammasome activation and function in liver disease. Nat Rev Gastroenterol Hepatol 12(7):387–400

    Article  CAS  PubMed  Google Scholar 

  21. Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A, Szabo G (2011) Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 54(1):133–144

    Article  CAS  PubMed  Google Scholar 

  22. Koyama Y, Brenner DA (2017) Liver inflammation and fibrosis. J Clin Invest 127(1):55–64

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lawan A, Bennett AM (2017) Mitogen-activated protein kinase regulation in hepatic metabolism. Trends Endocrinol Metab 28(12):868–878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Knebel B, Lehr S, Hartwig S, Haas J, Kaber G, Dicken HD, Susanto F, Bohne L, Jacob S, Nitzgen U, Passlack W, Muller-Wieland D, Kotzka J (2014) Phosphorylation of sterol regulatory element-binding protein (SREBP)-1c by p38 kinases, ERK and JNK influences lipid metabolism and the secretome of human liver cell line HepG2. Arch Physiol Biochem 120(5):216–227

    Article  CAS  PubMed  Google Scholar 

  25. Jiao P, Feng B, Li Y, He Q, Xu H (2013) Hepatic ERK activity plays a role in energy metabolism. Mol Cell Endocrinol 375(1–2):157–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Khodabandeloo H, Gorganifiruzjaee S, Panahi S, Meshkani R (2016) Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction. Transl Res 167(1):228–256

    Article  CAS  Google Scholar 

  27. Bieghs V, Trautwein C (2014) Innate immune signaling and gut-liver interactions in non-alcoholic fatty liver disease. Hepatobiliary Surg Nutr 3(6):377–385

    PubMed  PubMed Central  Google Scholar 

  28. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820

    Article  CAS  PubMed  Google Scholar 

  29. Kuo LH, Tsai PJ, Jiang MJ, Chuang YL, Yu L, Lai KTA, Tsai YS (2011) Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse. Diabetologia 54(1):168–179

    Article  CAS  PubMed  Google Scholar 

  30. Jia L, Vianna CR, Fukuda M, Berglund ED, Liu C, Tao C, Sun K, Liu T, Harper MJ, Lee CE, Lee S, Scherer PE, Elmquist JK (2014) Hepatocyte toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat Commun 5:3878

    Article  CAS  PubMed  Google Scholar 

  31. Inokuchi S, Tsukamoto H, Park E, Liu ZX, Brenner DA, Seki E (2011) Toll-like receptor 4 mediates alcohol-induced steatohepatitis through bone marrow-derived and endogenous liver cells in mice. Alcohol Clin Exp Res 35(8):1509–1518

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Carvalho FA, Koren O, Goodrich JK, Johansson ME, Nalbantoglu I, Aitken JD et al (2012) Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12(2):139–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Singh V, Chassaing B, Zhang L, San YB, Xiao X, Kumar M et al (2015) Microbiota-dependent hepatic lipogenesis mediated by stearoyl CoA desaturase 1 (SCD1) promotes metabolic syndrome in TLR5-deficient mice. Cell Metab 22(6):983–996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Arias-Loste MT, Iruzubieta P, Puente Á, Ramos D, Santa Cruz C, Estébanez Á, Llerena S, Alonso-Martín C, San Segundo D, Álvarez L, López Useros A, Fábrega E, López-Hoyos M, Crespo J (2016) Increased expression profile and functionality of TLR6 in peripheral blood mononuclear cells and hepatocytes of morbidly obese patients with non-alcoholic fatty liver disease. Int J Mol Sci 17(11). https://doi.org/10.3390/ijms17111878

  35. Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T, Ohnishi H, Olefsky JM, Brenner DA, Seki E (2010) Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 139(1):323–334

    Article  CAS  PubMed  Google Scholar 

  36. Handa P, Vemulakonda A, Kowdley KV, Uribe M, Méndez-Sánchez N (2016) Mitochondrial DNA from hepatocytes as a ligand for TLR9: drivers of nonalcoholic steatohepatitis? World J Gastroenterol 22(31):6965–6971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Garcia-Martinez I, Santoro N, Chen Y, Hoque R, Ouyang X, Caprio S, Shlomchik MJ, Coffman RL, Candia A, Mehal WZ (2016) Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest 126(3):859–864

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hoseini Z, Sepahvand F, Rashidi B, Sahebkar A, Masoudifar A, Mirzaei H (2017) NLRP3 inflammasome: its regulation and involvement in atherosclerosis. J Cell Physiol 233(3):2116–2132

    Article  PubMed  CAS  Google Scholar 

  39. Wree A, Mcgeough MD, Peña CA, Schlattjan M, Li H, Inzaugarat ME et al (2014) NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med 92(10):1069–1082

    Article  CAS  PubMed  Google Scholar 

  40. Mridha AR, Wree A, Robertson AAB, Yeh MM, Johnson CD, Van Rooyen DM et al (2017) NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol 66(5):1037–1046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482(7384):179–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. O'Neill LA, Golenbock D, Bowie AG (2013) The history of toll-like receptors [mdash] redefining innate immunity. Nat Rev Immunol 13(6):453–460

    Article  CAS  PubMed  Google Scholar 

  43. Yang L, Miura K, Zhang B, Matsushita H, Yang YM, Liang S, Song J, Roh YS, Seki E (2017) TRIF differentially regulates hepatic steatosis and inflammation/fibrosis in mice. Cell Mol Gastroenterol Hepatol 3(3):469–483

    Article  PubMed  PubMed Central  Google Scholar 

  44. Duparc T, Plovier H, Marrachelli VG, Hul MV, Essaghir A, Ståhlman M et al (2016) Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism. Gut 66(4):620–632

    Article  PubMed  CAS  Google Scholar 

  45. Castoldi A, Andrade-Oliveira V, Aguiar CF, Amano MT, Lee J, Miyagi MT et al (2017) Dectin-1 activation exacerbates obesity and insulin resistance in the absence of MyD88. Cell Rep 19(11):2272–2288

  46. Everard A, Geurts L, Caesar R, Van Hul M, Matamoros S, Duparc T et al (2014) Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat Commun 5:5648

    Article  CAS  PubMed  Google Scholar 

  47. Zhang W, Tang Z, Zhu X, Xia N, Zhao Y, Wang S, Cui S, Wang C (2015) TRAF1 knockdown alleviates palmitate-induced insulin resistance in HepG2 cells through NF-κB pathway. Biochem Biophys Res Commun 467(3):527–533

    Article  CAS  PubMed  Google Scholar 

  48. Xiang M, Wang PX, Wang AB, Zhang XJ, Zhang Y, Zhang P, Mei FH, Chen MH, Li H (2016) Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis. J Hepatol 64(6):1365–1377

    Article  CAS  PubMed  Google Scholar 

  49. Chen Z, Canet MJ, Liang S, Jiang L, Xiong Y, Yin L, Rui L (2015) Hepatocyte TRAF3 promotes insulin resistance and type 2 diabetes in mice with obesity. Mol Metab 4(12):951–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen Z, Shen H, Sun C, Yin L, Tang F, Zheng P et al (2015) Myeloid cell TRAF3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity. Am J Physiol Endocrinol Metab 308(6):460–469

    Article  CAS  Google Scholar 

  51. Chatzigeorgiou A, Seijkens T, Zarzycka B, Engel D, Poggi M, van den Berg S et al (2014) Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proc Natl Acad Sci U S A 111(7):2686–2691

  52. Gao L, Wang PX, Zhang Y, Yu CJ, Ji Y, Wang X, Zhang P, Jiang X, Jin H, Huang Z, Zhang ZR, Li H (2016) Tumor necrosis factor receptor-associated factor 5 (Traf5) acts as an essential negative regulator of hepatic steatosis. J Hepatol 65(1):125–136

    Article  CAS  PubMed  Google Scholar 

  53. Ceppo F, Jager J, Berthou F, Giorgetti-Peraldi S, Cormont M, Bost F, Tanti JF (2014) Implication of MAP kinases in obesity-induced inflammation and insulin resistance. Biol Aujourdhui 208(2):97–107

    Article  PubMed  Google Scholar 

  54. Kumphune S, Chattipakorn S, Chattipakorn N (2013) Roles of p38-MAPK in insulin resistant heart: evidence from bench to future bedside application. Curr Pharm Des 19(32):5742–5754

    Article  CAS  PubMed  Google Scholar 

  55. Kang HS, Okamoto K, Kim YS, Takeda Y, Bortner CD, Dang H, Wada T, Xie W, Yang XP, Liao G, Jetten AM (2011) Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance. Diabetes 60(1):177–188

    Article  CAS  PubMed  Google Scholar 

  56. Seki E (2014) TAK1-dependent autophagy: a suppressor of fatty liver disease and hepatic oncogenesis. Mol Cell Oncol 1(4):e968507

    Article  PubMed  PubMed Central  Google Scholar 

  57. Inokuchi-Shimizu S, Park EJ, Roh YS, Yang L, Zhang B, Song J et al (2014) TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J Clin Invest 124(8):3566–3578

  58. Morioka S, Sai K, Omori E, Ikeda Y, Matsumoto K, Ninomiya-Tsuji J (2016) TAK1 regulates hepatic lipid homeostasis through SREBP. Oncogene 35(29):3829–3838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schuster S, Feldstein AE (2017) NASH: novel therapeutic strategies targeting ASK1 in NASH. Nat Rev Gastroenterol Hepatol 14(6):329–330

    Article  CAS  PubMed  Google Scholar 

  60. Yamamoto E, Dong YF, Kataoka K, Yamashita T, Tokutomi Y, Matsuba S, Ichijo H, Ogawa H, Kim-Mitsuyama S (2008) Olmesartan prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, accompanied by apoptosis signal regulating kinase-1 inhibition. Hypertension 52(3):573–580

    Article  CAS  PubMed  Google Scholar 

  61. Zhang QY, Zhao LP, Tian XX, Yan CH, Li Y, Liu YX, Wang PX, Zhang XJ, Han YL (2017) The novel intracellular protein CREG inhibits hepatic steatosis, obesity and insulin resistance. Hepatology 66(3):834–854

    Article  CAS  PubMed  Google Scholar 

  62. Xie L, Wang PX, Zhang P, Zhang XJ, Zhao GN, Wang A, Guo J, Zhu X, Zhang Q, Li H (2016) DKK3 expression in hepatocytes defines susceptibility to liver steatosis and obesity. J Hepatol 65(1):113–124

    Article  CAS  PubMed  Google Scholar 

  63. Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ (2006) JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 43(1):163–172

    Article  CAS  PubMed  Google Scholar 

  64. Hu Y, Peng N, Lei D, Cheng F, Chen Y (2014) Impact of JNK inhibitor XG-102 in a diet-induced rat model of non-alcoholic steatohepatitis. Zhonghua Gan Zang Bing Za Zhi 22(12):948–952

    CAS  PubMed  Google Scholar 

  65. Yan H, Gao Y, Zhang Y (2017) Inhibition of JNK suppresses autophagy and attenuates insulin resistance in a rat model of nonalcoholic fatty liver disease. Mol Med Rep 15(1):180–186

    Article  CAS  PubMed  Google Scholar 

  66. Pereira S, Yu WQ, Moore J, Mori Y, Tsiani E, Giacca A (2016) Effect of a p38 MAPK inhibitor on FFA-induced hepatic insulin resistance in vivo. Nutr Diabetes 6:e210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee J, Sun C, Zhou Y, Lee J, Gokalp D, Herrema H, Park SW, Davis RJ, Ozcan U (2011) p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis. Nat Med 17(10):1251–1260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kujiraoka T, Satoh Y, Ayaori M, Shiraishi Y, Arainakaya Y, Hakuno D et al (2013) Hepatic extracellular signal–regulated kinase 2 suppresses endoplasmic reticulum stress and protects from oxidative stress and endothelial dysfunction. J Am Heart Assoc 2(4):e000361

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Khan AS, Subramaniam S, Dramane G, Khelifi D, Khan NA (2017) ERK1 and ERK2 activation modulates diet-induced obesity in mice. Biochimie 137:78–87

    Article  CAS  PubMed  Google Scholar 

  70. Wang PX, Zhang XJ, Li H (2016) Liver capsule: IRFs in hepatocytes: pathophysiology. Hepatology 63(5):1706

    Article  PubMed  Google Scholar 

  71. Zhao GN, Jiang DS, Li H (2015) Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease. Biochim Biophys Acta 1852(2):365–378

    Article  CAS  PubMed  Google Scholar 

  72. Chen J, Li J, Yiu JHC, Lam JKW, Wong CM, Dorweiler B, Xu A, Woo CW (2017) TRIF-dependent toll-like receptor signaling suppresses Scd1 transcription in hepatocytes and prevents diet-induced hepatic steatosis. Sci Signal 10(491):eaal3336

    Article  PubMed  CAS  Google Scholar 

  73. Wang XA, Zhang R, She ZG, Zhang XF, Jiang DS, Wang T, Gao L, Deng W, Zhang SM, Zhu LH, Guo S, Chen K, Zhang XD, Liu DP, Li H (2014) Interferon regulatory factor 3 constrains IKKβ/NF-κB signaling to alleviate hepatic steatosis and insulin resistance. Hepatology 59(3):870–885

    Article  CAS  PubMed  Google Scholar 

  74. Kumari M, Wang X, Lantier L, Lyubetskaya A, Eguchi J, Kang S, Tenen D, Roh HC, Kong X, Kazak L, Ahmad R, Rosen ED (2016) IRF3 promotes adipose inflammation and insulin resistance and represses browning. J Clin Invest 126(8):2839–2854

    Article  PubMed  PubMed Central  Google Scholar 

  75. Wang XA, Zhang R, Zhang S, Deng S, Jiang D, Zhong J, Yang L, Wang T, Hong S, Guo S, She ZG, Zhang XD, Li H (2013) Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance. Am J Physiol Endocrinol Metab 305(4):E485–E495

    Article  CAS  PubMed  Google Scholar 

  76. Wang XA, Zhang R, Jiang D, Deng W, Zhang S, Deng S, Zhong J, Wang T, Zhu LH, Yang L, Hong S, Guo S, Chen K, Zhang XF, She Z, Chen Y, Yang Q, Zhang XD, Li H (2013) Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice. Hepatology 58(2):603–616

    Article  CAS  PubMed  Google Scholar 

  77. Zámbó V, Simon-Szabó L, Szelényi P, Kereszturi E, Bánhegyi G, Csala M (2013) Lipotoxicity in the liver. World J Hepatol 5(10):550–557

    Article  PubMed  PubMed Central  Google Scholar 

  78. Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, Ray S, Majumdar SS, Bhattacharya S (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18(8):1279–1285

    Article  CAS  PubMed  Google Scholar 

  79. Zhao GN, Zhang P, Gong J, Zhang XJ, Wang PX, Yin M, Jiang Z, Shen LJ, Ji YX, Tong J, Wang Y, Wei QF, Wang Y, Zhu XY, Zhang X, Fang J, Xie Q, She ZG, Wang Z, Huang Z, Li H (2017) Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat Med 23(6):742–752

    Article  CAS  PubMed  Google Scholar 

  80. Wang PX, Ji YX, Zhang XJ, Zhao LP, Yan ZZ, Zhang P, Shen LJ, Yang X, Fang J, Tian S, Zhu XY, Gong J, Zhang X, Wei QF, Wang Y, Li J, Wan L, Xie Q, She ZG, Wang Z, Huang Z, Li H (2017) Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nat Med 23(4):439–449

    Article  CAS  PubMed  Google Scholar 

  81. Zhang P, Wang PX, Zhao LP, Zhang X, Ji YX, Zhang XJ, Fang C, Lu YX, Yang X, Gao MM, Zhang Y, Tian S, Zhu XY, Gong J, Ma XL, Li F, Wang Z, Huang Z, She ZG, Li H (2018) The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis. Nat Med 24(1):84–94

    Article  CAS  PubMed  Google Scholar 

  82. An S, Zhao LP, Shen LJ, Wang S, Zhang K, Qi Y, Zheng J, Zhang XJ, Zhu XY, Bao R, Yang L, Lu YX, She ZG, Tang YD (2017) USP18 protects against hepatic steatosis and insulin resistance via its DUB activity. Hepatology 66(6):1866–1884

    Article  CAS  PubMed  Google Scholar 

  83. Ji YX, Huang Z, Yang X, Wang X, Zhao LP, Wang PX, Zhang XJ, Alves-Bezerra M, Cai L, Zhang P, Lu YX, Bai L, Gao MM, Zhao H, Tian S, Wang Y, Huang ZX, Zhu XY, Zhang Y, Gong J, She ZG, Li F, Cohen DE, Li H (2018) The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis. Nat Med 24(2):213–223

    Article  CAS  PubMed  Google Scholar 

  84. Yan FJ, Zhang XJ, Wang WX, Ji YX, Wang PX, Yang Y, Gong J, Shen LJ, Zhu XY, Huang Z, Li H (2017) The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis. Hepatology 65(5):1492–1511

    Article  CAS  PubMed  Google Scholar 

  85. Wang PX, Zhang XJ, Luo P, Jiang X, Zhang P, Guo J, Zhao GN, Zhu X, Zhang Y, Yang S, Li H (2016) Hepatocyte TRAF3 promotes liver steatosis and systemic insulin resistance through targeting TAK1-dependent signalling. Nat Commun 7:10592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by grants from the National Science Fund for Distinguished Young Scholars (no. 81425005; H.L.), the Key Project of the National Natural Science Foundation (no. 81630011; H.L.), the Major Research Plan of the National Natural Science Foundation of China (no. 91639304, no. 91729303; H. L.), the Creative Groups Project of Hubei Province (no. 2016CFA010; H.L.), and the Hubei Science and Technology Support Project (no. 2018BEC473; H.L.).

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  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Lan Bai & Hongliang Li

  2. Institute of Model Animals of Wuhan University, Luojia Mount Wuchang, Wuhan, 430072, China

    Lan Bai & Hongliang Li

  3. Basic Medical School, Wuhan University, Wuhan, 430071, China

    Hongliang Li

  4. Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China

    Hongliang Li

  5. Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

    Hongliang Li

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Bai, L., Li, H. Innate immune regulatory networks in hepatic lipid metabolism. J Mol Med 97, 593–604 (2019). https://doi.org/10.1007/s00109-019-01765-1

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