慢性HBV感染与代谢功能障碍基础研究： 当前进展与争议

余博容; 陈源文

doi:10.12449/JCH240302

慢性HBV感染与代谢功能障碍基础研究：当前进展与争议

DOI: 10.12449/JCH240302

余博容,
陈源文^, ,

复旦大学附属华东医院消化内科，上海 200040

基金项目:

国家自然科学基金面上项目 (82270620);

上海市科学技术委员会项目 (22140901500)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：余博容负责文献检索、撰写文章；陈源文负责设计文章框架、修改和审校文章。

详细信息

通信作者:
陈源文， chenywhdgi@fudan.edu.cn （ORCID： 0000-0003-4210-007X）

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出版历程
- 收稿日期: 2023-11-21
- 录用日期: 2023-12-26
- 出版日期: 2024-03-20

Basic research on chronic hepatitis B virus infection and metabolic dysfunction： Advances and controversies

Borong YU,
Yuanwen CHEN^{,
,}

Department of Gastroenterology，Huadong Hospital Affiliated to Fudan University，Shanghai 200040，China

Research funding:

General Project of National Natural Science Foundation of China (82270620);

Project of Science and Technology Commission of Shanghai Municipality (22140901500)

More Information

Corresponding author: CHEN Yuanwen， chenywhdgi@fudan.edu.cn （ORCID： 0000-0003-4210-007X）

摘要

摘要: HBV被认为是一种“代谢病毒”，能影响多种代谢生命活动。慢性HBV感染与各种类型代谢功能障碍存在关联但仍无明确定论，对慢性HBV感染与代谢综合征、糖尿病、代谢相关脂肪性肝病等以代谢紊乱为特征的疾病之间相关性的机制仍知之甚少。目前主流观点认为，源自HBV基因组的HBx蛋白可能为HBV感染后介导机体代谢变化的重要环节，HBx可通过调节PPARγ、C/EBPα、SREBP和FATP2等蛋白的表达，影响机体糖、脂等物质的代谢，引起相关代谢功能障碍。非酒精性脂肪性肝病是代谢功能障碍在肝脏的最重要表现形式，由于其与HBV感染均可导致肝损伤，二者相互作用的研究备受关注，目前其关联仍存在较多争议，有待进一步探索。因此，本文详细阐述了当前慢性HBV感染与代谢功能障碍的相关研究进展，为后续的进一步研究提供思路。
- 乙型肝炎病毒 /
- 代谢综合征 /
- 非酒精性脂肪性肝病
Abstract: Hepatitis B virus （HBV） is considered a “metabolic virus” that can influence a variety of metabolic processes. There is still a lack of definite conclusion on the association between chronic HBV infection and the various types of metabolic dysfunction， and little is known about the mechanism of the association of chronic HBV infection with the diseases characterized by metabolic disorder， such as metabolic syndrome， diabetes， and metabolic associated fatty liver disease. Currently it is believed that hepatitis B x gene （HBx）， derived from HBV genome， might play an important role in mediating systemic metabolic alterations after HBV infection， and HBx influences the metabolism of carbohydrates and lipids and causes metabolic dysfunction by retgulating the expression profiles of the key proteins such as PPARγ， C/EBPα， SREBP， and FATP2. Nonalcoholic fatty liver disease （NAFLD） is the most severe manifestation of metabolic dysfunction in the liver， and since both NAFLD and HBV infection can cause liver injury， the research on the interaction between them has attracted more and more attention， with controversies requiring further exploration. Therefore， this article elaborates on the research advances in chronic HBV infection and metabolic dysfunction， so as to provide ideas for subsequent studies.
- Hepatitis B Virus /
- Metabolic Syndrome /
- Non-alcoholic Fatty Liver Disease

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参考文献(55)

[1]	SHLOMAI A, SHAUL Y. The“metabolovirus” model of hepatitis B virus suggests nutritional therapy as an effective anti-viral weapon[J]. Med Hypotheses, 2008, 71( 1): 53- 57. DOI: 10.1016/j.mehy.2007.08.032.
[2]	TANG L, COVERT E, WILSON E, et al. Chronic hepatitis B infection: a review[J]. JAMA, 2018, 319( 17): 1802- 1813. DOI: 10.1001/jama.2018.3795.
[3]	HOTAMISLIGIL GS. Inflammation and metabolic disorders[J]. Nature, 2006, 444( 7121): 860- 867. DOI: 10.1038/nature05485.
[4]	ALBERTI KG, ZIMMET P, SHAW J. Metabolic syndrome--a new world-wide definition. A consensus statement from the international diabetes federation[J]. Diabet Med, 2006, 23( 5): 469- 480. DOI: 10.1111/j.1464-5491.2006.01858.x.
[5]	AKHTAR S, JUSTICE LV, MORRISON CM, et al. Fictional first memories[J]. Psychol Sci, 2018, 29( 10): 1612- 1619. DOI: 10.1177/0956797618778831.
[6]	ALKHULAIFI F, DARKOH C. Meal timing, meal frequency and metabolic syndrome[J]. Nutrients, 2022, 14( 9). DOI: 10.3390/nu14091719.
[7]	LI Y, ZHAO Y, WU J. Serum HBV surface antigen positivity is associated with low prevalence of metabolic syndrome: A meta-analysis[J]. PLoS One, 2017, 12( 5): e0177713. DOI: 10.1371/journal.pone.0177713.
[8]	KIM KH, SHIN HJ, KIM K, et al. Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARgamma[J]. Gastroenterology, 2007, 132( 5): 1955- 1967. DOI: 10.1053/j.gastro.2007.03.039.
[9]	CHIANG CH, HUANG KC. Association between metabolic factors and chronic hepatitis B virus infection[J]. World J Gastroenterol, 2014, 20( 23): 7213- 7216. DOI: 10.3748/wjg.v20.i23.7213.
[10]	WANG SH, YEH SH, LIN WH, et al. Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B[J]. Hepatology, 2009, 50( 5): 1392- 1402. DOI: 10.1002/hep.23163.
[11]	ZHOU Y, CUI Y, DENG H, et al. Association between hepatitis B virus infection and metabolic syndrome: a retrospective cohort study in Shanghai, China[J]. BMC Public Health, 2014, 14: 516. DOI: 10.1186/1471-2458-14-516.
[12]	LI WC, LEE YY, CHEN IC, et al. Association between the hepatitis B and C viruses and metabolic diseases in patients stratified by age[J]. Liver Int, 2013, 33( 8): 1194- 1202. DOI: 10.1111/liv.12224.
[13]	TAN Y, ZHANG X, ZHANG W, et al. The influence of metabolic syndrome on the risk of hepatocellular carcinoma in patients with chronic hepatitis B infection in China[J]. Cancer Epidemiol Biomarkers Prev, 2019, 28( 12): 2038- 2046. DOI: 10.1158/1055-9965.EPI-19-0303.
[14]	PETERSEN MC, SHULMAN GI. Mechanisms of insulin action and insulin resistance[J]. Physiol Rev, 2018, 98( 4): 2133- 2223. DOI: 10.1152/physrev.00063.2017.
[15]	WANG CC, HSU CS, LIU CJ, et al. Association of chronic hepatitis B virus infection with insulin resistance and hepatic steatosis[J]. J Gastroenterol Hepatol, 2008, 23( 5): 779- 782. DOI: 10.1111/j.1440-1746.2007.05216.x.
[16]	LEE JG, LEE S, KIM YJ, et al. Association of chronic viral hepatitis B with insulin resistance[J]. World J Gastroenterol, 2012, 18( 42): 6120- 6126. DOI: 10.3748/wjg.v18.i42.6120.
[17]	WU YL, PENG XE, ZHU YB, et al. Hepatitis B virus X protein induces hepatic steatosis by enhancing the expression of liver fatty acid binding protein[J]. J Virol, 2016, 90( 4): 1729- 1740. DOI: 10.1128/JVI.02604-15.
[18]	KIM K, KIM KH, CHEONG J. Hepatitis B virus X protein impairs hepatic insulin signaling through degradation of IRS1 and induction of SOCS3[J]. PLoS One, 2010, 5( 3): e8649. DOI: 10.1371/journal.pone.0008649.
[19]	YIN W, CHEN B, YANG Y, et al. Association between maternal hepatitis B virus carrier and gestational diabetes mellitus: a retrospective cohort analysis[J]. Virol J, 2021, 18( 1): 226. DOI: 10.1186/s12985-021-01691-0.
[20]	ELKRIEF L, RAUTOU PE, SARIN S, et al. Diabetes mellitus in patients with cirrhosis: clinical implications and management[J]. Liver Int, 2016, 36( 7): 936- 948. DOI: 10.1111/liv.13115.
[21]	KINALSKI M, KUŹMICKI M, TELEJKO B, et al. Tumor necrosis factor-alpha system in patients with gestational diabetes[J]. Przegl Lek, 2006, 63( 4): 173- 175.
[22]	TILG H, ADOLPH TE, DUDEK M, et al. Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity[J]. Nat Metab, 2021, 3( 12): 1596- 1607. DOI: 10.1038/s42255-021-00501-9.
[23]	YASUMOTO J, KASAI H, YOSHIMURA K, et al. Hepatitis B virus prevents excessive viral production via reduction of cell death-inducing DFF45-like effectors[J]. J Gen Virol, 2017, 98( 7): 1762- 1773. DOI: 10.1099/jgv.0.000813.
[24]	ALVES-BEZERRA M, COHEN DE. Triglyceride metabolism in the liver[J]. Compr Physiol, 2017, 8( 1): 1- 8. DOI: 10.1002/cphy.c170012.
[25]	CURRIE E, SCHULZE A, ZECHNER R, et al. Cellular fatty acid metabolism and cancer[J]. Cell Metab, 2013, 18( 2): 153- 161. DOI: 10.1016/j.cmet.2013.05.017.
[26]	ARAIN SQ, TALPUR FN, CHANNA NA, et al. Serum lipids as an indicator for the alteration of liver function in patients with hepatitis B[J]. Lipids Health Dis, 2018, 17( 1): 36. DOI: 10.1186/s12944-018-0683-y.
[27]	DITTHAROT K, JITTORNTAM P, WILAIRAT P, et al. Urinary metabolomic profiling in chronic hepatitis B viral infection using gas chromatography/mass spectrometry[J]. Asian Pac J Cancer Prev, 2018, 19( 3): 741- 748. DOI: 10.22034/APJCP.2018.19.3.741.
[28]	LAMONTAGNE RJ, CASCIANO JC, BOUCHARD MJ. A broad investigation of the HBV-mediated changes to primary hepatocyte physiology reveals HBV significantly alters metabolic pathways[J]. Metabolism, 2018, 83: 50- 59. DOI: 10.1016/j.metabol.2018.01.007.
[29]	LI H, ZHU W, ZHANG L, et al. The metabolic responses to hepatitis B virus infection shed new light on pathogenesis and targets for treatment[J]. Sci Rep, 2015, 5: 8421. DOI: 10.1038/srep08421.
[30]	MIQUILENA-COLINA ME, LIMA-CABELLO E, SÁNCHEZ-CAMPOS S, et al. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C[J]. Gut, 2011, 60( 10): 1394- 1402. DOI: 10.1136/gut.2010.222844.
[31]	HUANG J, ZHAO L, YANG P, et al. Fatty acid translocase promoted hepatitis B virus replication by upregulating the levels of hepatic cytosolic calcium[J]. Exp Cell Res, 2017, 358( 2): 360- 368. DOI: 10.1016/j.yexcr.2017.07.012.
[32]	SCHOEMAN JC, HOU J, HARMS AC, et al. Metabolic characterization of the natural progression of chronic hepatitis B[J]. Genome Med, 2016, 8( 1): 64. DOI: 10.1186/s13073-016-0318-8.
[33]	WANG Y, WU T, HU D, et al. Intracellular hepatitis B virus increases hepatic cholesterol deposition in alcoholic fatty liver via hepatitis B core protein[J]. J Lipid Res, 2018, 59( 1): 58- 68. DOI: 10.1194/jlr.M079533.
[34]	WANG Y, HAO J, LIU X, et al. The mechanism of apoliprotein A1 down-regulated by Hepatitis B virus[J]. Lipids Health Dis, 2016, 15: 64. DOI: 10.1186/s12944-016-0232-5.
[35]	ZHU C, ZHU H, SONG H, et al. Hepatitis B virus inhibits the in vivo and in vitro synthesis and secretion of apolipoprotein C3[J]. Lipids Health Dis, 2017, 16( 1): 213. DOI: 10.1186/s12944-017-0607-2.
[36]	QIAO L, LUO GG. Human apolipoprotein E promotes hepatitis B virus infection and production[J]. PLoS Pathog, 2019, 15( 8): e1007874. DOI: 10.1371/journal.ppat.1007874.
[37]	FANG H, JUDD RL. Adiponectin regulation and function[J]. Compr Physiol, 2018, 8( 3): 1031- 1063. DOI: 10.1002/cphy.c170046.
[38]	YOON S, JUNG J, KIM T, et al. Adiponectin, a downstream target gene of peroxisome proliferator-activated receptor γ, controls hepatitis B virus replication[J]. Virology, 2011, 409( 2): 290- 298. DOI: 10.1016/j.virol.2010.10.024.
[39]	ZHANG Z, PAN Q, DUAN XY, et al. Fatty liver reduces hepatitis B virus replication in a genotype B hepatitis B virus transgenic mice model[J]. J Gastroenterol Hepatol, 2012, 27( 12): 1858- 1864. DOI: 10.1111/j.1440-1746.2012.07268.x.
[40]	HU D, WANG H, WANG H, et al. Non-alcoholic hepatic steatosis attenuates hepatitis B virus replication in an HBV-immunocompetent mouse model[J]. Hepatol Int, 2018, 12( 5): 438- 446. DOI: 10.1007/s12072-018-9877-7.
[41]	TONG X, SONG Y, YIN S, et al. Clinical impact and mechanisms of hepatitis B virus infection concurrent with non-alcoholic fatty liver disease[J]. Chin Med J(Engl), 2022, 135( 14): 1653- 1663. DOI: 10.1097/CM9.0000000000002310.
[42]	LIU Q, MU M, CHEN H, et al. Hepatocyte steatosis inhibits hepatitis B virus secretion via induction of endoplasmic reticulum stress[J]. Mol Cell Biochem, 2022, 477( 11): 2481- 2491. DOI: 10.1007/s11010-021-04143-z.
[43]	GAUDIERI S, RAUCH A, PFAFFEROTT K, et al. Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy[J]. Hepatology, 2009, 49( 4): 1069- 1082. DOI: 10.1002/hep.22773.
[44]	ZHANG RN, PAN Q, ZHANG Z, et al. Saturated fatty acid inhibits viral replication in chronic hepatitis B virus infection with nonalcoholic Fatty liver disease by toll-like receptor 4-mediated innate immune response[J]. Hepat Mon, 2015, 15( 5): e27909. DOI: 10.5812/hepatmon.15(5)2015.27909.
[45]	PICCININ E, VILLANI G, MOSCHETTA A. Metabolic aspects in NAFLD, NASH and hepatocellular carcinoma: the role of PGC1 coactivators[J]. Nat Rev Gastroenterol Hepatol, 2019, 16( 3): 160- 174. DOI: 10.1038/s41575-018-0089-3.
[46]	MAO Y, DA L, TANG H, et al. Hepatitis B virus X protein reduces starvation-induced cell death through activation of autophagy and inhibition of mitochondrial apoptotic pathway[J]. Biochem Biophys Res Commun, 2011, 415( 1): 68- 74. DOI: 10.1016/j.bbrc.2011.10.013.
[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. DOI: 10.1002/hep.28475.
[48]	WONG VW, WONG GL, CHU WC, et al. Hepatitis B virus infection and fatty liver in the general population[J]. J Hepatol, 2012, 56( 3): 533- 540. DOI: 10.1016/j.jhep.2011.09.013.
[49]	ZHU L, JIANG J, ZHAI X, et al. Hepatitis B virus infection and risk of non-alcoholic fatty liver disease: A population-based cohort study[J]. Liver Int, 2019, 39( 1): 70- 80. DOI: 10.1111/liv.13933.
[50]	MINAKARI M, MOLAEI M, SHALMANI HM, et al. Liver steatosis in patients with chronic hepatitis B infection: host and viral risk factors[J]. Eur J Gastroenterol Hepatol, 2009, 21( 5): 512- 516. DOI: 10.1097/MEG.0b013e328326792e.
[51]	LI JZ, YE LH, WANG DH, et al. The identify role and molecular mechanism of the MALAT1/hsa-mir-20b-5p/TXNIP axis in liver inflammation caused by CHB in patients with chronic HBV infection complicated with NAFLD[J]. Virus Res, 2021, 298: 198405. DOI: 10.1016/j.virusres.2021.198405.
[52]	MA J, SUN T, PARK S, et al. The role of hepatitis B virus X protein is related to its differential intracellular localization[J]. Acta Biochim Biophys Sin(Shanghai), 2011, 43( 8): 583- 588. DOI: 10.1093/abbs/gmr048.
[53]	BAI PS, XIA N, SUN H, et al. Pleiotrophin, a target of miR-384, promotes proliferation, metastasis and lipogenesis in HBV-related hepatocellular carcinoma[J]. J Cell Mol Med, 2017, 21( 11): 3023- 3043. DOI: 10.1111/jcmm.13213.
[54]	XU Z, ZHAI L, YI T, et al. Hepatitis B virus X induces inflammation and cancer in mice liver through dysregulation of cytoskeletal remodeling and lipid metabolism[J]. Oncotarget, 2016, 7( 43): 70559- 70574. DOI: 10.18632/oncotarget.12372.
[55]	LU Y, YANG X, KUANG Q, et al. HBx induced upregulation of FATP2 promotes the development of hepatic lipid accumulation[J]. Exp Cell Res, 2023, 430( 1): 113721. DOI: 10.1016/j.yexcr.2023.113721.