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Volume 40 Issue 4
Apr.  2024
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Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(4): 810-815

Mechanism of amino acid metabolism in nonalcoholic fatty liver disease

DOI: 10.12449/JCH240427

  • Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education，Chongqing Medical University，Chongqing 010000，China

Research funding:

General Project of National Natural Science Foundation of China (82273423);

Youth Fund of National Natural Science Foundation of China (82202501)

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  • Corresponding author: CHEN Juan， chenjuan2014@cqmu.edu.cn （ORCID： 0000-0001-6920-7972）
  • Received Date: 2023-08-01
  • Accepted Date: 2023-10-07
  • Published Date: 2024-04-25
    Abstract
  • Nonalcoholic fatty liver disease （NAFLD） is one of the most prevalent chronic liver diseases in the world， affecting about one quarter of the global population， and it is estimated that NAFLD will become the main indication for liver transplantation by 2030. NAFLD can lead to significant abnormalities in the levels of a variety of amino acids including branched-chain amino acids， thereby promoting the development and progression of NAFLD. These results suggest that in addition to glucose and lipid metabolism， amino acid metabolism also plays an important role in the progression of NAFLD. In order to systematically understand the role and mechanism of amino acid metabolism in NAFLD， this article reviews the research advances in amino acid metabolism in NAFLD. This article aims to explore the role and mechanism of amino acid metabolism in the progression of NAFLD， so as to provide ideas and a theoretical basis for clinical prevention and treatment.

     

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  • [1]
    ZHOU JH, ZHOU F, WANG WX, et al. Epidemiological features of NAFLD from 1999 to 2018 in China[J]. Hepatology, 2020, 71( 5): 1851- 1864. DOI: 10.1002/hep.31150.
    [2]
    CHALASANI N, YOUNOSSI Z, LAVINE JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association[J]. Hepatology, 2012, 55( 6): 2005- 2023. DOI: 10.1002/hep.25762.
    [3]
    SANO A, KAKAZU E, MOROSAWA T, et al. The profiling of plasma free amino acids and the relationship between serum albumin and plasma-branched chain amino acids in chronic liver disease: A single-center retrospective study[J]. J Gastroenterol, 2018, 53( 8): 978- 988. DOI: 10.1007/s00535-018-1435-5.
    [4]
    TANG SL, XIE JJ, WU WD, et al. High ammonia exposure regulates lipid metabolism in the pig skeletal muscle via mTOR pathway[J]. Sci Total Environ, 2020, 740: 139917. DOI: 10.1016/j.scitotenv.2020.139917.
    [5]
    ZHANG YS, LIN SY, PENG JY, et al. Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination[J]. Mol Cell, 2022, 82( 8): 1528- 1542. e 10. DOI: 10.1016/j.molcel.2022.01.021.
    [6]
    YAMAKADO M, TANAKA T, NAGAO KJ, et al. Plasma amino acid profile associated with fatty liver disease and co-occurrence of metabolic risk factors[J]. Sci Rep, 2017, 7( 1): 14485. DOI: 10.1038/s41598-017-14974-w.
    [7]
    GAGGINI M, CARLI F, ROSSO C, et al. Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance[J]. Hepatology, 2018, 67( 1): 145- 158. DOI: 10.1002/hep.29465.
    [8]
    PIETZNER M, BUDDE K, HOMUTH G, et al. Hepatic steatosis is associated with adverse molecular signatures in subjects without diabetes[J]. J Clin Endocrinol Metab, 2018, 103( 10): 3856- 3868. DOI: 10.1210/jc.2018-00999.
    [9]
    HASEGAWA T, IINO C, ENDO T, et al. Changed amino acids in NAFLD and liver fibrosis: A large cross-sectional study without influence of insulin resistance[J]. Nutrients, 2020, 12( 5): 1450. DOI: 10.3390/nu12051450.
    [10]
    KAIKKONEN JE, WÜRTZ P, SUOMELA E, et al. Metabolic profiling of fatty liver in young and middle-aged adults: Cross-sectional and prospective analyses of the Young Finns Study[J]. Hepatology, 2017, 65( 2): 491- 500. DOI: 10.1002/hep.28899.
    [11]
    GRZYCH G, VONGHIA L, BOUT MA, et al. Plasma BCAA changes in patients with NAFLD are sex dependent[J]. J Clin Endocrinol Metab, 2020, 105( 7): dgaa175. DOI: 10.1210/clinem/dgaa175.
    [12]
    GOFFREDO M, SANTORO N, TRICÒ D, et al. A branched-chain amino acid-related metabolic signature characterizes obese adolescents with non-alcoholic fatty liver disease[J]. Nutrients, 2017, 9( 7): 642. DOI: 10.3390/nu9070642.
    [13]
    CHASHMNIAM S, HASHEMI MADANI N, NOBAKHT MOTHLAGH GHOOCHANI BF, et al. The metabolome profiling of obese and non-obese individuals: Metabolically healthy obese and unhealthy non-obese paradox[J]. Iran J Basic Med Sci, 2020, 23( 2): 186- 194. DOI: 10.22038/IJBMS.2019.37885.9004.
    [14]
    SIGALA B, MCKEE C, SOEDA J, et al. Sympathetic nervous system catecholamines and neuropeptide Y neurotransmitters are upregulated in human NAFLD and modulate the fibrogenic function of hepatic stellate cells[J]. PLoS One, 2013, 8( 9): e72928. DOI: 10.1371/journal.pone.0072928.
    [15]
    NISHIMURA J, MASAKI T, ARAKAWA M, et al. Isoleucine prevents the accumulation of tissue triglycerides and upregulates the expression of PPARalpha and uncoupling protein in diet-induced obese mice[J]. J Nutr, 2010, 140( 3): 496- 500. DOI: 10.3945/jn.109.108977.
    [16]
    BAI J, GREENE E, LI WF, et al. Branched-chain amino acids modulate the expression of hepatic fatty acid metabolism-related genes in female broiler chickens[J]. Mol Nutr Food Res, 2015, 59( 6): 1171- 1181. DOI: 10.1002/mnfr.201400918.
    [17]
    LIU YX, DONG WB, SHAO J, et al. Branched-chain amino acid negatively regulates KLF15 expression via PI3K-AKT pathway[J]. Front Physiol, 2017, 8: 853. DOI: 10.3389/fphys.2017.00853.
    [18]
    GANCHEVA S, JELENIK T, ÁLVAREZ-HERNÁNDEZ E, et al. Interorgan metabolic crosstalk in human insulin resistance[J]. Physiol Rev, 2018, 98( 3): 1371- 1415. DOI: 10.1152/physrev.00015.2017.
    [19]
    NEWGARD CB, AN J, BAIN JR, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance[J]. Cell Metab, 2009, 9( 4): 311- 326. DOI: 10.1016/j.cmet.2009.02.002.
    [20]
    TAI ES, TAN MLS, STEVENS RD, et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men[J]. Diabetologia, 2010, 53( 4): 757- 767. DOI: 10.1007/s00125-009-1637-8.
    [21]
    HUFFMAN KM, SHAH SH, STEVENS RD, et al. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women[J]. Diabetes Care, 2009, 32( 9): 1678- 1683. DOI: 10.2337/dc08-2075.
    [22]
    PALMER ND, STEVENS RD, ANTINOZZI PA, et al. Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study[J]. J Clin Endocrinol Metab, 2015, 100( 3): E463- E468. DOI: 10.1210/jc.2014-2357.
    [23]
    CHENG SL, WIKLUND P, AUTIO R, et al. Adipose tissue dysfunction and altered systemic amino acid metabolism are associated with non-alcoholic fatty liver disease[J]. PLoS One, 2015, 10( 10): e0138889. DOI: 10.1371/journal.pone.0138889.
    [24]
    LAKE AD, NOVAK P, SHIPKOVA P, et al. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease[J]. Amino Acids, 2015, 47( 3): 603- 615. DOI: 10.1007/s00726-014-1894-9.
    [25]
    HONDA T, ISHIGAMI M, LUO FQ, et al. Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice[J]. Metabolism, 2017, 69: 177- 187. DOI: 10.1016/j.metabol.2016.12.013.
    [26]
    NIE CX, HE T, ZHANG WJ, et al. Branched chain amino acids: Beyond nutrition metabolism[J]. Int J Mol Sci, 2018, 19( 4): 954. DOI: 10.3390/ijms19040954.
    [27]
    HAUFE S, WITT H, ENGELI S, et al. Branched-chain and aromatic amino acids, insulin resistance and liver specific ectopic fat storage in overweight to obese subjects[J]. Nutr Metab Cardiovasc Dis, 2016, 26( 7): 637- 642. DOI: 10.1016/j.numecd.2016.03.013.
    [28]
    VAN DEN BERG EH, FLORES-GUERRERO JL, GRUPPEN EG, et al. Non-alcoholic fatty liver disease and risk of incident type 2 diabetes: Role of circulating branched-chain amino acids[J]. Nutrients, 2019, 11( 3): 705. DOI: 10.3390/nu11030705.
    [29]
    IWAO M, GOTOH K, ARAKAWA M, et al. Supplementation of branched-chain amino acids decreases fat accumulation in the liver through intestinal microbiota-mediated production of acetic acid[J]. Sci Rep, 2020, 10( 1): 18768. DOI: 10.1038/s41598-020-75542-3.
    [30]
    WHITE PJ, MCGARRAH RW, GRIMSRUD PA, et al. The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase[J]. Cell Metab, 2018, 27( 6): 1281- 1293. e 7. DOI: 10.1016/j.cmet.2018.04.015.
    [31]
    ZARFESHANI A, NGO S, SHEPPARD AM. Leucine alters hepatic glucose/lipid homeostasis via the myostatin-AMP-activated protein kinase pathway-potential implications for nonalcoholic fatty liver disease[J]. Clin Epigenetics, 2014, 6( 1): 27. DOI: 10.1186/1868-7083-6-27.
    [32]
    CELINSKI K, KONTUREK PC, SLOMKA M, et al. Effects of treatment with melatonin and tryptophan on liver enzymes, parameters of fat metabolism and plasma levels of cytokines in patients with non-alcoholic fatty liver disease: 14 months follow up[J]. J Physiol Pharmacol, 2014, 65( 1): 75- 82.
    [33]
    RITZE Y, BÁRDOS G, HUBERT A, et al. Effect of tryptophan supplementation on diet-induced non-alcoholic fatty liver disease in mice[J]. Br J Nutr, 2014, 112( 1): 1- 7. DOI: 10.1017/S0007114514000440.
    [34]
    JI Y, GAO Y, CHEN H, et al. Indole-3-acetic acid alleviates nonalcoholic fatty liver disease in mice via attenuation of hepatic lipogenesis, and oxidative and inflammatory stress[J]. Nutrients, 2019, 11( 9): 2062. DOI: 10.3390/nu11092062.
    [35]
    ZHAO ZH, XIN FZ, XUE YQ, et al. Indole-3-propionic acid inhibits gut dysbiosis and endotoxin leakage to attenuate steatohepatitis in rats[J]. Exp Mol Med, 2019, 51( 9): 1- 14. DOI: 10.1038/s12276-019-0304-5.
    [36]
    CHEN Y, LI CL, LIU LY, et al. Serum metabonomics of NAFLD plus T2DM based on liquid chromatography-mass spectrometry[J]. Clin Biochem, 2016, 49( 13-14): 962- 966. DOI: 10.1016/j.clinbiochem.2016.05.016.
    [37]
    STOJANOVIĆ M, TODOROVIĆ D, ŠĆEPANOVIĆ L, et al. Subchronic methionine load induces oxidative stress and provokes biochemical and histological changes in the rat liver tissue[J]. Mol Cell Biochem, 2018, 448( 1-2): 43- 50. DOI: 10.1007/s11010-018-3311-2.
    [38]
    KALHAN SC, EDMISON J, MARCZEWSKI S, et al. Methionine and protein metabolism in non-alcoholic steatohepatitis: Evidence for lower rate of transmethylation of methionine[J]. Clin Sci(Lond), 2011, 121( 4): 179- 189. DOI: 10.1042/CS20110060.
    [39]
    VEENA J, MURAGUNDLA A, SIDGIDDI S, et al. Non-alcoholic fatty liver disease: Need for a balanced nutritional source[J]. Br J Nutr, 2014, 112( 11): 1858- 1872. DOI: 10.1017/S0007114514002591.
    [40]
    AISSA AF, TRYNDYAK V, DE CONTI A, et al. Effect of methionine-deficient and methionine-supplemented diets on the hepatic one-carbon and lipid metabolism in mice[J]. Mol Nutr Food Res, 2014, 58( 7): 1502- 1512. DOI: 10.1002/mnfr.201300726.
    [41]
    ZUBIETE-FRANCO I, GARCÍA-RODRÍGUEZ JL, MARTÍNEZ-UÑA M, et al. Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis[J]. J Hepatol, 2016, 64( 2): 409- 418. DOI: 10.1016/j.jhep.2015.08.037.
    [42]
    LYMAN RL, GIOTAS C, MEDWADOWSKI B, et al. Effect of low methionine, choline deficient diets upon major unsaturated phosphatidyl choline fractions of rat liver and plasma[J]. Lipids, 1975, 10( 3): 157- 167. DOI: 10.1007/BF02534154.
    [43]
    ALARCÓN-VILA C, INSAUSTI-URKIA N, TORRES S, et al. Dietary and genetic disruption of hepatic methionine metabolism induce acid sphingomyelinase to promote steatohepatitis[J]. Redox Biol, 2023, 59: 102596. DOI: 10.1016/j.redox.2022.102596.
    [44]
    YAO ZM, VANCE DE. The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes[J]. J Biol Chem, 1988, 263( 6): 2998- 3004.
    [45]
    WELTMAN MD, FARRELL GC, LIDDLE C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation[J]. Gastroenterology, 1996, 111( 6): 1645- 1653. DOI: 10.1016/s0016-5085(96)70028-8.
    [46]
    YANG YM, CAI JS, YANG X, et al. Dysregulated m6A modification promotes lipogenesis and development of non-alcoholic fatty liver disease and hepatocellular carcinoma[J]. Mol Ther, 2022, 30( 6): 2342- 2353. DOI: 10.1016/j.ymthe.2022.02.021.
    [47]
    LECLERCQ IA, FARRELL GC, FIELD J, et al. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis[J]. J Clin Invest, 2000, 105( 8): 1067- 1075. DOI: 10.1172/JCI8814.
    [48]
    KULINSKI A, VANCE DE, VANCE JE. A choline-deficient diet in mice inhibits neither the CDP-choline pathway for phosphatidylcholine synthesis in hepatocytes nor apolipoprotein B secretion[J]. J Biol Chem, 2004, 279( 23): 23916- 23924. DOI: 10.1074/jbc.M312676200.
    [49]
    JIN R, BANTON S, TRAN VT, et al. Amino acid metabolism is altered in adolescents with nonalcoholic fatty liver disease-an untargeted, high resolution metabolomics study[J]. J Pediatr, 2016, 172: 14- 19.e5. DOI: 10.1016/j.jpeds.2016.01.026.
    [50]
    GOBEIL É, MALTAIS-PAYETTE I, TABA N, et al. Mendelian randomization analysis identifies blood tyrosine levels as a biomarker of non-alcoholic fatty liver disease[J]. Metabolites, 2022, 12( 5): 440. DOI: 10.3390/metabo12050440.
    [51]
    PASTORE A, ALISI A, DI GIOVAMBERARDINO G, et al. Plasma levels of homocysteine and cysteine increased in pediatric NAFLD and strongly correlated with severity of liver damage[J]. Int J Mol Sci, 2014, 15( 11): 21202- 21214. DOI: 10.3390/ijms151121202.
    [52]
    TRICÒ D, BIANCALANA E, SOLINI A. Protein and amino acids in nonalcoholic fatty liver disease[J]. Curr Opin Clin Nutr Metab Care, 2021, 24( 1): 96- 101. DOI: 10.1097/MCO.0000000000000706.
    [53]
    ABU-SERIE MM, EL-GAMAL BA, EL-KERSH MA, et al. Investigation into the antioxidant role of arginine in the treatment and the protection for intralipid-induced non-alcoholic steatohepatitis[J]. Lipids Health Dis, 2015, 14: 128. DOI: 10.1186/s12944-015-0124-0.
    [54]
    VOLOSHIN I, HAHN-OBERCYGER M, ANAVI S, et al. L-arginine conjugates of bile acids-a possible treatment for non-alcoholic fatty liver disease[J]. Lipids Health Dis, 2014, 13: 69. DOI: 10.1186/1476-511X-13-69.
    [55]
    HARDING HP, ZHANG YH, ZENG H, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress[J]. Mol Cell, 2003, 11( 3): 619- 633. DOI: 10.1016/s1097-2765(03)00105-9.
    [56]
    DONG J, QIU H, GARCIA-BARRIO M, et al. Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain[J]. Mol Cell, 2000, 6( 2): 269- 279. DOI: 10.1016/s1097-2765(00)00028-9.
    [57]
    GUO FF, CAVENER DR. The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid[J]. Cell Metab, 2007, 5( 2): 103- 114. DOI: 10.1016/j.cmet.2007.01.001.
    [58]
    YUAN JT, YU ZR, GAO JL, et al. Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation[J]. Redox Biol, 2022, 49: 102224. DOI: 10.1016/j.redox.2021.102224.
    [59]
    LIU GY, SABATINI DM. mTOR at the nexus of nutrition, growth, ageing and disease[J]. Nat Rev Mol Cell Biol, 2020, 21( 4): 183- 203. DOI: 10.1038/s41580-019-0199-y.
    [60]
    JEWELL JL, RUSSELL RC, GUAN KL. Amino acid signalling upstream of mTOR[J]. Nat Rev Mol Cell Biol, 2013, 14( 3): 133- 139. DOI: 10.1038/nrm3522.
    [61]
    PORSTMANN T, SANTOS CR, GRIFFITHS B, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth[J]. Cell Metab, 2008, 8( 3): 224- 236. DOI: 10.1016/j.cmet.2008.07.007.
    [62]
    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. DOI: 10.1002/hep.28431.
    [63]
    MAUVOISIN D, ROCQUE G, ARFA O, et al. Role of the PI3-kinase/mTor pathway in the regulation of the stearoyl CoA desaturase(SCD1) gene expression by insulin in liver[J]. J Cell Commun Signal, 2007, 1( 2): 113- 125. DOI: 10.1007/s12079-007-0011-1.
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