酒精性脂肪肝的线粒体作用机制研究进展

doi:10.3969/j.issn.1004-616x.2021.06.014

摘要/Abstract

摘要： 酒精性脂肪肝是世界范围内肝脏相关疾病发病和死亡的主要驱动因素之一。酒精摄入会负向调控肝脏正常的脂质代谢，而肝脏对酒精最早和最常见的不良反应是肝脏脂肪变性，其严重程度被认为与酒精性肝病中晚期进展密切相关。线粒体作为内源性活性氧的主要生成位点和生物能量代谢的关键场所之一，在调节肝细胞氧化还原和脂质代谢方面起着重要作用。然而，酒精诱导线粒体内活性氧的大量生成会直接或间接导致线粒体功能障碍，进而抑制线粒体β氧化，造成大量脂肪酸在肝内异常累积，最终导致酒精性脂肪肝。本文主要从酒精诱导肝脏线粒体氧化应激、线粒体β氧化、线粒体自噬、缺氧和线粒体靶向抗氧化剂等角度探讨了其与酒精性脂肪肝相关的潜在发病机制，并回顾了与线粒体相关的其他转录因子对酒精诱导的肝脏脂质累积的作用。

关键词: 酒精, 脂肪变性, 氧化应激, β氧化

中图分类号:

R730.231

曹家豪, 彭越, 段佳琪, 刘桥松, 刘启玲, 秦绪军. 酒精性脂肪肝的线粒体作用机制研究进展[J]. 癌变·畸变·突变, 2021, 33(6): 475-481.

参考文献

[1] GBD ALCOHOL COLLABORATORS. Alcohol use and burden for 195 countries and territories, 1990-2016:a systematic analysis for the Global Burden of Disease Study 2016[J]. Lancet, 2018, 392(10152):1015-1035.
[2] SHARMA P, ARORA A. Clinical presentation of alcoholic liver disease and non-alcoholic fatty liver disease:spectrum and diagnosis[J]. Transl Gastroenterol Hepatol, 2020, 5:19.
[3] JEON S, CARR R. Alcohol effects on hepatic lipid metabolism[J]. J Lipid Res, 2020, 61(4):470-479.
[4] SEITZ H K, BATALLER R, CORTEZ-PINTO H, et al. Alcoholic liver disease[J]. Nat Rev Dis Primers, 2018, 4(1):16.
[5] ROTH N C, QIN J. Histopathology of alcohol-related liver diseases[J]. Clin Liver Dis, 2019, 23(1):11-23.
[6] LAKSHMAN R, SHAH R, REYES-GORDILLO K, et al. Synergy between NAFLD and AFLD and potential biomarkers[J]. Clin Res Hepatol Gastroenterol, 2015, 39(Sup 1):S29-S34.
[7] MA K L, CHEN G, LI W H, et al. Mitophagy, mitochondrial homeostasis, and cell fate[J]. Front Cell Dev Biol, 2020, 8:467.
[8] ABDELMEGEED M A, HA S K, CHOI Y, et al. Role of CYP2E1 in mitochondrial dysfunction and hepatic injury by alcohol and non-alcoholic substances[J]. Curr Mol Pharmacol, 2017, 10(3):207-225.
[9] TESCHKE R. Alcoholic liver disease:current mechanistic aspects with focus on their clinical relevance[J]. Biomedicines, 2019, 7(3):E68.
[10] LV Y, SO K F, XIAO J. Liver regeneration and alcoholic liver disease[J]. Ann Transl Med, 2020, 8(8):567.
[11] KONG L Z, CHANDIMALI N, HAN Y H, et al. Pathogenesis, early diagnosis, and therapeutic management of alcoholic liver disease[J]. Int J Mol Sci, 2019, 20(11):E2712.
[12] LIEBER C S, RUBIN E, DECARLI L M. Hepatic microsomal ethanol oxidizing system (MEOS):differentiation from alcohol dehydrogenase and NADPH oxidase[J]. Biochem Biophys Res Commun, 1970, 40(4):858-865.
[13] SEITZ H K, MUELLER S. The role of Cytochrom P4502E1 in Alcoholic Liver Disease and alcohol mediated carcinogenesis[J]. Z Gastroenterol, 2019, 57(1):37-45.
[14] ALKADI H. A review on free radicals and antioxidants[J]. Infect Disord Drug Targets, 2020, 20(1):16-26.
[15] SIES H, JONES D P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents[J]. Nat Rev Mol Cell Biol, 2020, 21(7):363-383.
[16] GARCíA-SáNCHEZ A, MIRANDA-DíAZ A G, CARDONA-MUÑOZ E G. The role of oxidative stress in physiopathology and pharmacological treatment with pro-and antioxidant properties in chronic diseases[J]. Oxid Med Cell Longev, 2020, 2020:2082145.
[17] ISRAEL P, VICENTE C, ELENA S M, et al. Oxidative stress, plant natural antioxidants, and obesity[J]. Int J Mol Sci, 2021, 22(4):1786.
[18] ZHANG Y F, WONG H S. Are mitochondria the main contributor of reactive oxygen species in cells?[J]. J Exp Biol, 2021, 224(Pt 5):jeb221606.
[19] KITADA M, XU J, OGURA Y, et al. Manganese superoxide dismutase dysfunction and the pathogenesis of kidney disease[J]. Front Physiol, 2020, 11:755.
[20] LIU Y, ZHAO Y, WANG J L. Fenton/Fenton-like processes with in situ production of hydrogen peroxide/hydroxyl radical for degradation of emerging contaminants:advances and prospects[J]. J Hazard Mater, 2021, 404(Sup B):124191.
[21] PRASUN P, GINEVIC I, OISHI K. Mitochondrial dysfunction in nonalcoholic fatty liver disease and alcohol related liver disease[J]. Transl Gastroenterol Hepatol, 2021, 6:4.
[22] LU Y, CEDERBAUM A I. Autophagy protects against CYP2E1/chronic ethanol-induced hepatotoxicity[J]. Biomolecules, 2015, 5(4):2659-2674.
[23] ZENG T, ZHANG C L, ZHAO N, et al. Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver[J]. Redox Biol, 2018, 14:295-304.
[24] ARTEEL G E, IIMURO Y, YIN M, et al. Chronic enteral ethanol treatment causes hypoxia in rat liver tissue in vivo[J]. Hepatology, 1997, 25(4):920-926.
[25] WANG X D, WU D F, YANG L L, et al. Cytochrome P4502E1 potentiates ethanol induction of hypoxia and HIF-1α in vivo[J]. Free Radic Biol Med, 2013, 63:175-186.
[26] HE T, AI M, ZHAO X H, et al. Inducible nitric oxide synthase mediates hypoxia-induced hypoxia-inducible factor-1 alpha activation and vascular endothelial growth factor expression in oxygen-induced retinopathy[J]. Pathobiology, 2007, 74(6):336-343.
[27] ZELICKSON B R, BENAVIDES G A, JOHNSON M S, et al. Nitric oxide and hypoxia exacerbate alcohol-induced mitochondrial dysfunction in hepatocytes[J]. Biochim Biophys Acta, 2011, 1807(12):1573-1582.
[28] SHARMA N, PASALA M S, PRAKASH A. Mitochondrial DNA:Epigenetics and environment[J]. Environ Mol Mutagen, 2019, 60(8):668-682.
[29] YAN C J, DUANMU X Y, ZENG L, et al. Mitochondrial DNA:distribution, mutations, and elimination[J]. Cells, 2019, 8(4):379.
[30] BALLARD J W O, TOWARNICKI S G. Mitochondria, the gut microbiome and ROS[J]. Cell Signal, 2020, 75:109737.
[31] MA X W, MCKEEN T, ZHANG J H, et al. Role and mechanisms of mitophagy in liver diseases[J]. Cells, 2020, 9(4):837.
[32] GARZA-LOMBó C, PAPPA A, PANAYIOTIDIS M I, et al. Redox homeostasis, oxidative stress and mitophagy[J]. Mitochondrion, 2020, 51:105-117.
[33] SEKINE S. PINK₁ import regulation at a crossroad of mitochondrial fate:the molecular mechanisms of PINK₁ import[J]. J Biochem, 2020, 167(3):217-224.
[34] ZHAO H C, LIU S, ZHAO H, et al. Protective effects of fucoidan against ethanol-induced liver injury through maintaining mitochondrial function and mitophagy balance in rats[J]. Food Funct, 2021, 12(9):3842-3854.
[35] WILLIAMS J A, DING W X. A mechanistic review of mitophagy and its role in protection against alcoholic liver disease[J]. Biomolecules, 2015, 5(4):2619-2642.
[36] WILLIAMS J A, NI H M, DING Y F, et al. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice[J]. Am J Physiol Gastrointest Liver Physiol, 2015, 309(5):G324-G340.
[37] EID N, ITO Y, HORIBE A, et al. Ethanol-induced mitophagy in liver is associated with activation of the PINK₁-Parkin pathway triggered by oxidative DNA damage[J]. Histol Histopathol, 2016, 31(10):1143-1159.
[38] DING M G, FENG N, TANG D S, et al. Melatonin prevents Drp1-mediated mitochondrial fission in diabetic hearts through SIRT1-PGC1α pathway[J]. J Pineal Res, 2018, 65(2):e12491.
[39] PURI R, CHENG X T, LIN M Y, et al. Defending stressed mitochondria:uncovering the role of MUL1 in suppressing neuronal mitophagy[J]. Autophagy, 2020, 16(1):176-178.
[40] LUO Y D, MA J J, LU W Q. The significance of mitochondrial dysfunction in cancer[J]. Int J Mol Sci, 2020, 21(16):E5598.
[41] REN X Y, ZOU L L, ZHANG X, et al. Redox signaling mediated by thioredoxin and glutathione systems in the central nervous system[J]. Antioxid Redox Signal, 2017, 27(13):989-1010.
[42] KUMAR S M, HARIDOSS M, SWAMINATHAN K, et al. The effects of changes in glutathione levels through exogenous agents on intracellular cysteine content and protein adduct formation in chronic alcohol-treated VL17A cells[J]. Toxicol Mech Methods, 2017, 27(2):128-135.
[43] LASH L H. Diverse roles of mitochondria in renal injury from environmental toxicants and therapeutic drugs[J]. Int J Mol Sci, 2021, 22(8):4172.
[44] LIEBER C S. Hepatic and metabolic effects of ethanol:pathogenesis and prevention[J]. Ann Med, 1994, 26(5):325-330.
[45] GARCíA-RUIZ C, MORALES A, COLELL A, et al. Feeding S-adenosyl-L-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes[J]. Hepatology, 1995, 21(1):207-214.
[46] LATIPÄÄ P M, KÄRKI T T, HILTUNEN J K, et al. Regulation of palmitoylcarnitine oxidation in isolated rat liver mitochondria. Role of the redox state of NAD(H)[J]. Biochim Biophys Acta, 1986, 875(2):293-300.
[47] KĘPKA A, ZWIERZ P, CHOJNOWSKA S, et al. Relation of plasma carnitine and aminotransferases to alcohol dose and time of dependence[J]. Alcohol, 2019, 81:62-69.
[48] ZHONG Z, LEMASTERS J J. A unifying hypothesis linking hepatic adaptations for ethanol metabolism to the proinflammatory and profibrotic events of alcoholic liver disease[J]. Alcohol Clin Exp Res, 2018, 42(11):2072-2089.
[49] PENNA F, BONELLI G, BACCINO F M, et al. Cytotoxic properties of clofibrate and other peroxisome proliferators:relevance to cancer progression[J]. Curr Med Chem, 2010, 17(4):309-320.
[50] FISCHER M, YOU M, MATSUMOTO M, et al. Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice[J]. J Biol Chem, 2003, 278(30):27997-28004.
[51] VILLENA J A. New insights into PGC-1 coactivators:redefining their role in the regulation of mitochondrial function and beyond[J]. Febs J, 2015, 282(4):647-672.
[52] VALLE I, áLVAREZ-BARRIENTOS A, ARZA E, et al. PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells[J]. Cardiovasc Res, 2005, 66(3):562-573.
[53] HU M, WANG F, LI X, et al. Regulation of hepatic lipin-1 by ethanol:role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice[J]. Hepatology, 2012, 55(2):437-446.
[54] YOU M, JOGASURIA A, LEE K, et al. Signal transduction mechanisms of alcoholic fatty liver disease:emer ging role of lipin-1[J]. Curr Mol Pharmacol, 2017, 10(3):226-236.
[55] BI L J, JIANG Z A, ZHOU J Y. The role of lipin-1 in the pathogenesis of alcoholic fatty liver[J]. Alcohol, 2015, 50(2):146-151.
[56] HU M, YIN H Q, MITRA M S, et al. Hepatic-specific lipin-1 deficiency exacerbates experimental alcohol-induced steatohepatitis in mice[J]. Hepatology, 2013, 58(6):1953-1963.
[57] GUO C, SHANGGUAN Y, ZHANG M R, et al. Rosmarinic acid alleviates ethanol-induced lipid accumulation by repressing fatty acid biosynthesis[J]. Food Funct, 2020, 11(3):2094-2106.
[58] LIANGPUNSAKUL S, ROSS R A, CRABB D W. Activation of carbohydrate response element-binding protein by ethanol[J]. J Investig Med, 2013, 61(2):270-277.
[59] SHEARN C T, SMATHERS R L, JIANG H, et al. Increased dietary fat contributes to dysregulation of the LKB₁/AMPK pathway and increased damage in a mouse model of early-stage ethanol-mediated steatosis[J]. J Nutr Biochem, 2013, 24(8):1436-1445.
[60] JIANG Z A, ZHOU J Y, ZHOU D F, et al. The adiponectin-SIRT1-AMPK pathway in alcoholic fatty liver disease in the rat[J]. Alcohol Clin Exp Res, 2015, 39(3):424-433.
[61] AJMO J M, LIANG X M, ROGERS C Q, et al. Resveratrol alleviates alcoholic fatty liver in mice[J]. Am J Physiol Gastrointest Liver Physiol, 2008, 295(4):G833-G842.
[62] SHEN Z, LIANG X M, ROGERS C Q, et al. Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice[J]. Am J Physiol Gastrointest Liver Physiol, 2010, 298(3):G364-G374.
[63] LIU Y L, ZHAO C Q, XIAO J, et al. Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury[J]. Sci Rep, 2016, 6:31026.
[64] ZHU S L, MA L, WU Y Z, et al. FGF21 treatment ameliorates alcoholic fatty liver through activation of AMPK-SIRT1 pathway[J]. Acta Biochim Biophys Sin (Shanghai), 2014, 46(12):1041-1048.
[65] SHULGA N, PASTORINO J G. Ethanol sensitizes mitochondria to the permeability transition by inhibiting deacetylation of cyclophilin-D mediated by sirtuin-3[J]. J Cell Sci, 2010, 123(Pt 23):4117-4127.
[66] XUE L, XU F, MENG L J, et al. Acetylation-dependent regulation of mitochondrial ALDH2 activation by SIRT3 mediates acute ethanol-induced ENOS activation[J]. FEBS Lett, 2012, 586(2):137-142.
[67] NISHIYAMA Y, GODA N, MAI K N, et al. HIF-1α induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice[J]. J Hepatol, 2012, 56(2):441-447.
[68] NATH B, LEVIN I, CSAK T, et al. Hepatocyte-specific hypoxia-inducible factor-1α is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice[J]. Hepatology, 2011, 53(5):1526-1537.