非酒精性脂肪性肝病相关肝细胞癌发病机制研究进展
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摘要
非酒精性脂肪性肝病(NAFLD)是以肝脏脂肪堆积异常、炎症和肝细胞功能障碍为特征的肝脏疾病的总称,是全世界最常见的慢性肝脏疾病之一。近年来,NAFLD相关肝细胞癌(NAFLD-HCC)数量日益增多,对NAFLD-HCC发病机制的研究也日益深入。NAFLD-HCC发病机制的复杂性成为其有效治疗的主要障碍,主要与代谢综合征、肠道微生物、基因、促炎细胞因子、脂肪细胞因子、自噬等相关,深入研究其发病机制可为NAFLD-HCC的诊断和治疗提供更大的帮助。
Non-alcoholic fatty liver disease( NAFLD) includes a series of liver diseases characterized by abnormal liver fat accumulation,inflammation and hepatocyte dysfuntion. It is one of the most common chronic liver diseases in the world.In recent years,the number of NAFLD-related hepatocellular carcinoma( NAFLD-HCC) has been increasing,and the study of NAFLD-HCC pathogenesis has been continuously deepening. The complex factors of the pathogenesis of NAFLD-HCC have been the main obstacle to the effective treatment,including metabolic syndrome,intestinal microbes,genes,proinflammatory cytokines,adipocytokines,autophagy,etc. Further study of the pathogenesis of NAFLD-HCC may provide greater help to the diagnosis and treatment.
Non-alcoholic fatty liver disease( NAFLD) includes a series of liver diseases characterized by abnormal liver fat accumulation,inflammation and hepatocyte dysfuntion. It is one of the most common chronic liver diseases in the world.In recent years,the number of NAFLD-related hepatocellular carcinoma( NAFLD-HCC) has been increasing,and the study of NAFLD-HCC pathogenesis has been continuously deepening. The complex factors of the pathogenesis of NAFLD-HCC have been the main obstacle to the effective treatment,including metabolic syndrome,intestinal microbes,genes,proinflammatory cytokines,adipocytokines,autophagy,etc. Further study of the pathogenesis of NAFLD-HCC may provide greater help to the diagnosis and treatment.
引文
[1] Kitade H,Chen G,Ni Y,et al. Nonalcoholic Fatty Liver Disease and Insulin Resistance:New Insights and Potential New Treatments[J]. Nutrients,2017,9(4). pii:E387.
[2] Perumpail BJ,Khan MA,Yoo ER,et al. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease[J]. World J Gastroenterol,2017,23(47):8263-8276.
[3] Younossi ZM,Koenig AB,Abdelatif D,et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence,incidence,and outcomes[J]. Hepatology,2016,64(1):73-84.
[4] Wainwright P,Byrne CD. Bidirectional Relationships and Disconnects between NAFLD and Features of the Metabolic Syndrome[J]. Int J Mol Sci,2016,17(3):367.
[5] Scalera A,Tarantino G. Could metabolic syndrome lead to hepatocarcinoma via non-alcoholic fatty liver disease?[J]. World J Gastroenterol,2014,20(28):9217-9228.
[6] Agosti P,SabbàC,Mazzocca A. Emerging metabolic risk factors in hepatocellular carcinoma and their influence on the liver microenvironment[J]. Biochim Biophys Acta Mol Basis Dis,2018,1864(2):607-617.
[7] Mantovani A,Targher G. Type 2 diabetes mellitus and risk of hepatocellular carcinoma:Spotlight on nonalcoholic fatty liver disease[J]. Ann Transl Med,2017,5(13):270.
[8] Marseglia L,Manti S,D'Angelo G,et al. Oxidative stress in obesity:A critical component in human diseases[J]. Int J Mol Sci,2014,16(1):378-400.
[9] Zhang X. NAFLD Related-HCC:The Relationship with Metabolic Disorders[J]. Adv Exp Med Biol,2018,1061:55-62.
[10] Fujiwara N,Nakagawa H,Enooku K,et al. CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity[J]. Gut,2018,67(8):1493-1504.
[11] Benbow JH,Thompson KJ,Cope HL,et al. Diet-Induced Obesity Enhances Progression of Hepatocellular Carcinoma through Tenascin-C/Toll-Like Receptor 4 Signaling[J]. Am J Pathol,2016,186(1):145-158.
[12] Inoue-Yamauchi A,Itagaki H,Oda H. Eicosapentaenoic acid attenuates obesity-related hepatocellular carcinogenesis[J].Carcinogenesis,2018,39(1):28-35.
[13] Suzuki-Kemuriyama N,Matsuzaka T,Kuba M,et al. Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice[J]. PLo S One,2016,11(6):e0157580.
[14] Perumpail RB,Wong RJ,Ahmed A,et al. Hepatocellular Carcinoma in the Setting of Non-cirrhotic Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome:US Experience[J]. Dig Dis Sci,2015,60(10):3142-3148.
[15] Miyauchi S,Miyake T,Miyazaki M,et al. Free testosterone concentration is inversely associated with markers of liver fibrosis in men with type 2 diabetes mellitus[J]. Endocr J,2017,64(12):1137-1142.
[16] Arab JP,Arrese M,Trauner M. Recent Insights into the Pathogenesis of Nonalcoholic Fatty Liver Disease[J]. Annu Rev Pathol,2018,13:321-350.
[17] Massoud O,Charlton M. Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma[J]. Clin Liver Dis,2018,22(1):201-211.
[18] Marengo A,Rosso C,Bugianesi E. Liver Cancer:Connections with Obesity,Fatty Liver,and Cirrhosis[J]. Annu Rev Med,2016,67:103-117.
[19] Tang R,Liu H,Yuan Y,et al. Genetic factors associated with risk of metabolic syndrome and hepatocellular carcinoma[J]. Oncotarget,2017,8(21):35403-35411.
[20] K9roˇglu E,Canbakan B,Atay K,et al. Role of oxidative stress and insulin resistance in disease severity of non-alcoholic fatty liver disease[J]. Turk J Gastroenterol,2016,27(4):361-366.
[21] Baffy G,Brunt EM,Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease:An emerging menace[J]. J Hepatol,2012,56(6):1384-1391.
[22] Baumeier C,Schlüter L,Saussenthaler S,et al. Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease[J]. Mol Metab,2017,6(10):1254-1263.
[23] Xu M,Zheng XM,Jiang F,et al. MicroRNA-190b regulates lipid metabolism and insulin sensitivity by targeting IGF-1 and ADAMTS9in non-alcoholic fatty liver disease[J]. J Cell Biochem,2018,119(7):5864-5874.
[24] Xie G,Wang X,Liu P,et al. Distinctly altered gut microbiota in the progression of liver disease[J]. Oncotarget,2016,7(15):19355-19366.
[25] Mao JW,Tang HY,Zhao T,et al. Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease[J]. Int J Clin Exp Pathol,2015,8(4):3648-3658.
[26] Li DY,Yang M,Edwards S,et al. Nonalcoholic fatty liver disease:For better or worse,blame the gut microbiota?[J]. JPEN J Parenter Enteral Nutr,2013,37(6):787-793.
[27] Douhara A,Moriya K,Yoshiji H,et al. Reduction of endotoxin attenuates liver fibrosis through suppression of hepatic stellate cell activation and remission of intestinal permeability in a rat nonalcoholic steatohepatitis model[J]. Mol Med Rep,2015,11(3):1693-1700.
[28] Dapito DH,Mencin A,Gwak GY,et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4[J]. Cancer Cell,2012,21(4):504-516.
[29] Bigorgne AE,John B,Ebrahimkhani MR,et al. TLR4-Dependent Secretion by Hepatic Stellate Cells of the Neutrophil-Chemoattractant CXCL1 Mediates Liver Response to Gut Microbiota[J]. PLo S One,2016,11(3):e0151063.
[30] Ponziani FR,Bhoori S,Castelli C,et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease[J/OL]. Hepatology,2018.[2018-07-26]. https://aasldpubs. onlinelibrary. wiley. com/doi/10.1002/hep. 30036.[published online ahead of print Apr 17,2018]
[31] Achiwa K,Ishigami M,Ishizu Y,et al. DSS colitis promotes tumorigenesis and fibrogenesis in a choline-deficient high-fat dietinduced NASH mouse model[J]. Biochem Biophys Res Commun,2016,470(1):15-21.
[32] Tao X,Wang N,Qin W. Gut Microbiota and Hepatocellular Carcinoma[J]. Gastrointestinal Tumors,2015 2(1):33-40.
[33] Pant K,Yadav AK,Gupta P,et al. Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1 pathway in hepatic cancer cells[J]. Redox Biol,2017,12:340-349.
[34] Feng Q,Chen WD,Wang YD. Gut Microbiota:An Integral Moderator in Health and Disease[J]. Front Microbiol,2018,9:151.
[35] Lade A,Noon LA,Friedman SL. Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis,hepatic fibrosis,and cancer[J]. Curr Opin Oncol,2014,26(1):100-107.
[36] Yoshimoto S,Loo TM,Atarashi K,et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome[J]. Nature,2013,499(7456):97-101.
[37] Ray K. Gut microbiota:Obesity-induced microbial metabolite promotes HCC[J]. Nat Rev Gastroenterol Hepatol,2013,10(8):442.
[38] Loo TM,Kamachi F,Watanabe Y,et al. Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity[J]. Cancer Discov,2017,7(5):522-538.
[39] Di Costanzo A,Belardinilli F,Bailetti D,et al. Evaluation of Polygenic Determinants of Non-Alcoholic Fatty Liver Disease(NAFLD)By a Candidate Genes Resequencing Strategy[J]. Sci Rep,2018,8(1):3702.
[40] Wang X,Liu Z,Wang K,et al. Additive Effects of the Risk Alleles of PNPLA3 and TM6SF2 on Non-alcoholic Fatty Liver Disease(NAFLD)in a Chinese Population[J]. Front Genet,2016,7:140.
[41] Romeo S,Kozlitina J,Xing C,et al. Genetic variation in PNPLA3confers susceptibility to nonalcoholic fatty liver disease[J]. Nat Genet,2008,40(12):1461-1465.
[42] Pirazzi C,Valenti L,Motta BM,et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells[J]. Hum Mol Genet,2014,23(15):4077-4085.
[43] Donati B,Motta BM,Pingitore P,et al. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3expression and liver damage[J]. Hepatology,2016,63(3):787-798.
[44] Ehrhardt N,Doche ME,Chen S,et al. Hepatic Tm6sf2 overexpression affects cellular Apo B-trafficking,plasma lipid levels,hepatic steatosis and atherosclerosis[J]. Hum Mol Genet,2017,26(14):2719-2731.
[45] Krawczyk M,Rau M,Schattenberg JM,et al. Combined effects of the PNPLA3 rs738409,TM6SF2 rs58542926,and MBOAT7rs641738 variants on NAFLD severity:A multicenter biopsybased study[J]. Lipid Res,2017,58(1):247-255.
[46] Koo BK,Joo SK,Kim D,et al. Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease[J]. J Gastroenterol Hepatol,2018,33(6):1277-1285.
[47] Eslam M,Mangia A,Berg T,et al. Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes[J]. Hepatology,2016,64(1):34-46.
[48] Zhou Y,LlauradóG,Ore2iˇc M,et al. Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2[J]. J Hepatol,2015,62(3):657-663.
[49] Jindal A,BruzzìS,Sutti S,et al. Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis(NASH)[J].Exp Mol Pathol,2015,99(1):155-162.
[50] Chiyonobu N,Shimada S,Akiyama Y,et al. Fatty Acid Binding Protein 4(FABP4)Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors[J]. Am J Pathol,2018,188(5):1213-1224.
[51] Hotamisligil GS,Bernlohr DA. Metabolic functions of FABPs—mechanisms and therapeutic implications[J]. Nat Rev Endocrinol,2015,11(10):592-605.
[52] Chen X,Ling Y,Wei Y,et al. Dual regulation of HMGB1 by combined JNK1/2-ATF2 axis with miR-200 family in nonalcoholic steatohepatitis in mice[J]. FASEB J,2018,32(5):2722-2734.
[53] Kessler SM,Simon Y,Gemperlein K,et al. Fatty acid elongation in non-alcoholic steatohepatitis and hepatocellular carcinoma[J].Int J Mol Sci,2014,15(4):5762-5773.
[54] Wieser V,Moschen AR,Tilg H. Adipocytokines and hepatocellular carcinoma[J]. Dig Dis,2012,30(5):508-513.
[55] Adolph TE,Grander C,Grabherr F,et al. Adipokines and NonAlcoholic Fatty Liver Disease:Multiple Interactions[J]. Int J Mol Sci,2017,18(8). pii:E1649.
[56] Gatselis NK,Ntaios G,Makaritsis K,et al. Adiponectin:A key playmaker adipocytokine in non-alcoholic fatty liver disease[J].Clin Exp Med,2013,14(2):121-131.
[57] Polyzos SA,Kountouras J,Mantzoros CS. Leptin in nonalcoholic fatty liver disease:A narrative review[J]. Metabolism,2015,64(1):60-78.
[58] Czaja MJ. Function of Autophagy in Nonalcoholic Fatty Liver Disease[J]. Dig Dis Sci,2016,61(5):1304-1313.
[59] Lin YC,Chang PF,Lin HF,et al. Variants in the autophagy-related gene IRGM confer susceptibility to non-alcoholic fatty liver disease by modulating lipophagy[J]. J Hepatol,2016,65(6):1209-1216.
[60] Wu WKK,Zhang L,Chan MTV. Autophagy,NAFLD and NAFLDRelated HCC[J]. Adv Exp Med Biol,2018,1061:127-138.
[61] Inokuchi-Shimizu S,Park EJ,Roh YS,et al. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis[J]. J Clin Invest,2014,124(8):3566-3578.
[2] Perumpail BJ,Khan MA,Yoo ER,et al. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease[J]. World J Gastroenterol,2017,23(47):8263-8276.
[3] Younossi ZM,Koenig AB,Abdelatif D,et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence,incidence,and outcomes[J]. Hepatology,2016,64(1):73-84.
[4] Wainwright P,Byrne CD. Bidirectional Relationships and Disconnects between NAFLD and Features of the Metabolic Syndrome[J]. Int J Mol Sci,2016,17(3):367.
[5] Scalera A,Tarantino G. Could metabolic syndrome lead to hepatocarcinoma via non-alcoholic fatty liver disease?[J]. World J Gastroenterol,2014,20(28):9217-9228.
[6] Agosti P,SabbàC,Mazzocca A. Emerging metabolic risk factors in hepatocellular carcinoma and their influence on the liver microenvironment[J]. Biochim Biophys Acta Mol Basis Dis,2018,1864(2):607-617.
[7] Mantovani A,Targher G. Type 2 diabetes mellitus and risk of hepatocellular carcinoma:Spotlight on nonalcoholic fatty liver disease[J]. Ann Transl Med,2017,5(13):270.
[8] Marseglia L,Manti S,D'Angelo G,et al. Oxidative stress in obesity:A critical component in human diseases[J]. Int J Mol Sci,2014,16(1):378-400.
[9] Zhang X. NAFLD Related-HCC:The Relationship with Metabolic Disorders[J]. Adv Exp Med Biol,2018,1061:55-62.
[10] Fujiwara N,Nakagawa H,Enooku K,et al. CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity[J]. Gut,2018,67(8):1493-1504.
[11] Benbow JH,Thompson KJ,Cope HL,et al. Diet-Induced Obesity Enhances Progression of Hepatocellular Carcinoma through Tenascin-C/Toll-Like Receptor 4 Signaling[J]. Am J Pathol,2016,186(1):145-158.
[12] Inoue-Yamauchi A,Itagaki H,Oda H. Eicosapentaenoic acid attenuates obesity-related hepatocellular carcinogenesis[J].Carcinogenesis,2018,39(1):28-35.
[13] Suzuki-Kemuriyama N,Matsuzaka T,Kuba M,et al. Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice[J]. PLo S One,2016,11(6):e0157580.
[14] Perumpail RB,Wong RJ,Ahmed A,et al. Hepatocellular Carcinoma in the Setting of Non-cirrhotic Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome:US Experience[J]. Dig Dis Sci,2015,60(10):3142-3148.
[15] Miyauchi S,Miyake T,Miyazaki M,et al. Free testosterone concentration is inversely associated with markers of liver fibrosis in men with type 2 diabetes mellitus[J]. Endocr J,2017,64(12):1137-1142.
[16] Arab JP,Arrese M,Trauner M. Recent Insights into the Pathogenesis of Nonalcoholic Fatty Liver Disease[J]. Annu Rev Pathol,2018,13:321-350.
[17] Massoud O,Charlton M. Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma[J]. Clin Liver Dis,2018,22(1):201-211.
[18] Marengo A,Rosso C,Bugianesi E. Liver Cancer:Connections with Obesity,Fatty Liver,and Cirrhosis[J]. Annu Rev Med,2016,67:103-117.
[19] Tang R,Liu H,Yuan Y,et al. Genetic factors associated with risk of metabolic syndrome and hepatocellular carcinoma[J]. Oncotarget,2017,8(21):35403-35411.
[20] K9roˇglu E,Canbakan B,Atay K,et al. Role of oxidative stress and insulin resistance in disease severity of non-alcoholic fatty liver disease[J]. Turk J Gastroenterol,2016,27(4):361-366.
[21] Baffy G,Brunt EM,Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease:An emerging menace[J]. J Hepatol,2012,56(6):1384-1391.
[22] Baumeier C,Schlüter L,Saussenthaler S,et al. Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease[J]. Mol Metab,2017,6(10):1254-1263.
[23] Xu M,Zheng XM,Jiang F,et al. MicroRNA-190b regulates lipid metabolism and insulin sensitivity by targeting IGF-1 and ADAMTS9in non-alcoholic fatty liver disease[J]. J Cell Biochem,2018,119(7):5864-5874.
[24] Xie G,Wang X,Liu P,et al. Distinctly altered gut microbiota in the progression of liver disease[J]. Oncotarget,2016,7(15):19355-19366.
[25] Mao JW,Tang HY,Zhao T,et al. Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease[J]. Int J Clin Exp Pathol,2015,8(4):3648-3658.
[26] Li DY,Yang M,Edwards S,et al. Nonalcoholic fatty liver disease:For better or worse,blame the gut microbiota?[J]. JPEN J Parenter Enteral Nutr,2013,37(6):787-793.
[27] Douhara A,Moriya K,Yoshiji H,et al. Reduction of endotoxin attenuates liver fibrosis through suppression of hepatic stellate cell activation and remission of intestinal permeability in a rat nonalcoholic steatohepatitis model[J]. Mol Med Rep,2015,11(3):1693-1700.
[28] Dapito DH,Mencin A,Gwak GY,et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4[J]. Cancer Cell,2012,21(4):504-516.
[29] Bigorgne AE,John B,Ebrahimkhani MR,et al. TLR4-Dependent Secretion by Hepatic Stellate Cells of the Neutrophil-Chemoattractant CXCL1 Mediates Liver Response to Gut Microbiota[J]. PLo S One,2016,11(3):e0151063.
[30] Ponziani FR,Bhoori S,Castelli C,et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease[J/OL]. Hepatology,2018.[2018-07-26]. https://aasldpubs. onlinelibrary. wiley. com/doi/10.1002/hep. 30036.[published online ahead of print Apr 17,2018]
[31] Achiwa K,Ishigami M,Ishizu Y,et al. DSS colitis promotes tumorigenesis and fibrogenesis in a choline-deficient high-fat dietinduced NASH mouse model[J]. Biochem Biophys Res Commun,2016,470(1):15-21.
[32] Tao X,Wang N,Qin W. Gut Microbiota and Hepatocellular Carcinoma[J]. Gastrointestinal Tumors,2015 2(1):33-40.
[33] Pant K,Yadav AK,Gupta P,et al. Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1 pathway in hepatic cancer cells[J]. Redox Biol,2017,12:340-349.
[34] Feng Q,Chen WD,Wang YD. Gut Microbiota:An Integral Moderator in Health and Disease[J]. Front Microbiol,2018,9:151.
[35] Lade A,Noon LA,Friedman SL. Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis,hepatic fibrosis,and cancer[J]. Curr Opin Oncol,2014,26(1):100-107.
[36] Yoshimoto S,Loo TM,Atarashi K,et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome[J]. Nature,2013,499(7456):97-101.
[37] Ray K. Gut microbiota:Obesity-induced microbial metabolite promotes HCC[J]. Nat Rev Gastroenterol Hepatol,2013,10(8):442.
[38] Loo TM,Kamachi F,Watanabe Y,et al. Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity[J]. Cancer Discov,2017,7(5):522-538.
[39] Di Costanzo A,Belardinilli F,Bailetti D,et al. Evaluation of Polygenic Determinants of Non-Alcoholic Fatty Liver Disease(NAFLD)By a Candidate Genes Resequencing Strategy[J]. Sci Rep,2018,8(1):3702.
[40] Wang X,Liu Z,Wang K,et al. Additive Effects of the Risk Alleles of PNPLA3 and TM6SF2 on Non-alcoholic Fatty Liver Disease(NAFLD)in a Chinese Population[J]. Front Genet,2016,7:140.
[41] Romeo S,Kozlitina J,Xing C,et al. Genetic variation in PNPLA3confers susceptibility to nonalcoholic fatty liver disease[J]. Nat Genet,2008,40(12):1461-1465.
[42] Pirazzi C,Valenti L,Motta BM,et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells[J]. Hum Mol Genet,2014,23(15):4077-4085.
[43] Donati B,Motta BM,Pingitore P,et al. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3expression and liver damage[J]. Hepatology,2016,63(3):787-798.
[44] Ehrhardt N,Doche ME,Chen S,et al. Hepatic Tm6sf2 overexpression affects cellular Apo B-trafficking,plasma lipid levels,hepatic steatosis and atherosclerosis[J]. Hum Mol Genet,2017,26(14):2719-2731.
[45] Krawczyk M,Rau M,Schattenberg JM,et al. Combined effects of the PNPLA3 rs738409,TM6SF2 rs58542926,and MBOAT7rs641738 variants on NAFLD severity:A multicenter biopsybased study[J]. Lipid Res,2017,58(1):247-255.
[46] Koo BK,Joo SK,Kim D,et al. Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease[J]. J Gastroenterol Hepatol,2018,33(6):1277-1285.
[47] Eslam M,Mangia A,Berg T,et al. Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes[J]. Hepatology,2016,64(1):34-46.
[48] Zhou Y,LlauradóG,Ore2iˇc M,et al. Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2[J]. J Hepatol,2015,62(3):657-663.
[49] Jindal A,BruzzìS,Sutti S,et al. Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis(NASH)[J].Exp Mol Pathol,2015,99(1):155-162.
[50] Chiyonobu N,Shimada S,Akiyama Y,et al. Fatty Acid Binding Protein 4(FABP4)Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors[J]. Am J Pathol,2018,188(5):1213-1224.
[51] Hotamisligil GS,Bernlohr DA. Metabolic functions of FABPs—mechanisms and therapeutic implications[J]. Nat Rev Endocrinol,2015,11(10):592-605.
[52] Chen X,Ling Y,Wei Y,et al. Dual regulation of HMGB1 by combined JNK1/2-ATF2 axis with miR-200 family in nonalcoholic steatohepatitis in mice[J]. FASEB J,2018,32(5):2722-2734.
[53] Kessler SM,Simon Y,Gemperlein K,et al. Fatty acid elongation in non-alcoholic steatohepatitis and hepatocellular carcinoma[J].Int J Mol Sci,2014,15(4):5762-5773.
[54] Wieser V,Moschen AR,Tilg H. Adipocytokines and hepatocellular carcinoma[J]. Dig Dis,2012,30(5):508-513.
[55] Adolph TE,Grander C,Grabherr F,et al. Adipokines and NonAlcoholic Fatty Liver Disease:Multiple Interactions[J]. Int J Mol Sci,2017,18(8). pii:E1649.
[56] Gatselis NK,Ntaios G,Makaritsis K,et al. Adiponectin:A key playmaker adipocytokine in non-alcoholic fatty liver disease[J].Clin Exp Med,2013,14(2):121-131.
[57] Polyzos SA,Kountouras J,Mantzoros CS. Leptin in nonalcoholic fatty liver disease:A narrative review[J]. Metabolism,2015,64(1):60-78.
[58] Czaja MJ. Function of Autophagy in Nonalcoholic Fatty Liver Disease[J]. Dig Dis Sci,2016,61(5):1304-1313.
[59] Lin YC,Chang PF,Lin HF,et al. Variants in the autophagy-related gene IRGM confer susceptibility to non-alcoholic fatty liver disease by modulating lipophagy[J]. J Hepatol,2016,65(6):1209-1216.
[60] Wu WKK,Zhang L,Chan MTV. Autophagy,NAFLD and NAFLDRelated HCC[J]. Adv Exp Med Biol,2018,1061:127-138.
[61] Inokuchi-Shimizu S,Park EJ,Roh YS,et al. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis[J]. J Clin Invest,2014,124(8):3566-3578.