References

nogr

Экспериментальная и клиническая гастроэнтерология

Experimental and Clinical Gastroenterology

1682-8658

«Global Media Technologies»

10.31146/1682-8658-ecg-192-8-167-174

nogr-1725

Research Article

ОБЗОР

REVIEW

Факторы риска прогрессирования неалкогольной жировой болезни печени

Nonalcoholic liver disease: review with a focus on risks of progression

https://orcid.org/0000-0002-7628-8851

Теплюк

Д. А.

Teplyuk

D. A.

Теплюк Дарья Андреевна, гастроэнтеролог, ассистент кафедры терапии

119991, Москва, ул. Большая Пироговская, д. 2, стр. 4

Daria A. Teplyuk, gastroenterologist, assistant of the department of therapy

bld.4, 2 Bolshaya Pirogovskaya street, Moscow, 119991

teplyouk@gmail.com

https://orcid.org/0000-0002-1724-4760

Семенистая

М. Ч.

Semenistaya

M. Ch.

Семенистая Марианна Чавдаровна, гастроэнтеролог, ассистент кафедры терапии

119991, Москва, ул. Большая Пироговская, д. 2, стр. 4

Marianna Ch. Semenistaya, gastroenterologist, assistant of the department of therapy

bld.4, 2 Bolshaya Pirogovskaya street, Moscow, 119991

Scopus Author ID: 57188634836

Сороколетов

С. М.

Sorokoletov

S. M.

Сороколетов Сергей Михайлович, проф. д. м. н., заместитель главного врача по медицинской части (по терапевтической помощи)

125284, Москва, 2-й Боткинский пр-д, 5

Sergey M. Sorokoletov, prof. Doctor of Medical Sciences, Deputy Chief Physician for Medical (for Therapeutic Assistance);

5, 2nd Botkinsky pr-d, Moscow, 125284

Scopus Author ID: 6508202807

https://orcid.org/0000-0001-8736-5851

Лазебник

Л. Б.

Lazebnik

L. B.

Лазебник Леонид Борисович, д. м. н., профессор кафедры поликлинической терапии

127473, г. Москва, ул. Делегатская, д. 20, стр. 1

Leonid B. Lazebnik, MD, DSc, Professor of the Department of Polyclinic Therapy

20 Delegatskaya street, Moscow, 127473

Scopus Author ID: 7005446863

https://orcid.org/0000-0001-5031-9798

Павлов

Ч. С.

Pavlov

Ch. S.

Павлов Чавдар Савов, д. м. н., проф. зав. кафедрой терапии; руководитель клиники гастроэнтерологии

119991, Москва, ул. Большая Пироговская, д. 2, стр. 4; 125284, Москва, 2-й Боткинский пр-д, 5

Chavdar S. Pavlov, MD, PhD, prof. head Department of Therapy; Head of the Gastroenterology Clinic

bld.4, 2 Bolshaya Pirogovskaya street, Moscow, 119991; 5, 2nd Botkinsky pr-d, Moscow, 125284

Scopus Author ID: 57196355076;

ResearcherID: E-7020-2017

ФГАОУ ВО «Первый Московский государственный медицинский университет им. И. М. Сеченова»РоссияI. M. Sechenov First Moscow State Medical University, Ministry of Health of RussiaRussian Federation

ГБУЗ ГКБ им. С. П. Боткина ДЗМРоссияBotkin Moscow City HospitalRussian Federation

ФГБОУ ВО МГМСУ им. А. И. Евдокимова Минздрава РоссииРоссияA. I. Evdokimov, Moscow State University of Medicine and Dentistry, Ministry of Health of RussiaRussian Federation

ФГАОУ ВО «Первый Московский государственный медицинский университет им. И. М. Сеченова»; ГБУЗ ГКБ им. С. П. Боткина ДЗМРоссияI. M. Sechenov First Moscow State Medical University, Ministry of Health of Russia; Botkin Moscow City HospitalRussian Federation

2021

19112021

08167174

2021

Теплюк Д.А., Семенистая М.Ч., Сороколетов С.М., Лазебник Л.Б., Павлов Ч.С.

Teplyuk D.A., Semenistaya M.C., Sorokoletov S.M., Lazebnik L.B., Pavlov C.S.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.nogr.org/jour/article/view/1725

Неалкогольная жировая болезнь печени (НАЖБП) — заболевание, этиология которого включает не только метаболические, но и этнические, генетические и экологические факторы. Многогранность этиологии и многочисленные пути патогенеза, приводящие в конечном счете к появлению жировых капель в гепатоцитах, воспалительному процессу и фиброзу паренхимы печени, а также частая сердечно- сосудистая и метаболическая коморбидность пациентов, затрудняют стратификацию рисков и оценку прогноза у данных больных. Особо стоит вопрос терапии, поскольку в отношении фармакотерапевтических подходов пока не достигнут международный консенсус, а изменение образа жизни, хотя и считается эффективным методом лечения, в рутинной клинической практике не выполняется больными. В данном обзоре рассматриваются актуальные вопросы как диагностики и риски прогрессирования заболевания, так и возможности его терапии.

Nonalcoholic fatty liver disease (NAFLD) is a disease which etiology is related to various metabolic, ethnic, genetic and even ecologic factors. Complexity of etiology and multiply pathogenesis ways, leading eventually to the lipid droplets appearance in hepatocytes, infl ammation process and parenchyma fi brosis in liver, and also frequent cardiometabolic comorbidities, together make diffi cult risks stratifi cation and prognosis evaluation in NAFLD patients. Another matter is a question of NAFLD therapy, since unifi ed pharmacotherapy approaches are not yet adopted worldwide, and lifestyle modifi cation being accepted as an eff ective therapeutic approach, is not followed by patients in real world setting. Current review is dedicated to the consideration of NAFLD diagnostics, its risk of progression and existing therapeutical capabilities.

НАЖБПжировой гепатозНАСГстеатогепатитпрогрессированиеизменение образа жизнифармакотерапияобзор

NAFLDfatty liverNASHsteatohepatitisprognosisprogressionlifestyle modifi cationpharmacotherapyreview

References1

Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease- Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016 Jul;64(1):73–84. doi: 10.1002/hep.28431. Epub 2016 Feb 22. PMID: 26707365.

Rich NE, Oji S, Mufti AR, et al. Racial and Ethnic Disparities in Nonalcoholic Fatty Liver Disease Prevalence, Severity, and Outcomes in the United States: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018 Feb;16(2):198–210.e2. doi: 10.1016/j.cgh.2017.09.041. Epub 2017 Sep 29. PMID: 28970148; PMCID: PMC5794571.

Allen AM, Th erneau TM, Larson JJ, Coward A, Somers VK, Kamath PS. Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: A 20 year-community study. Hepatology. 2018 May;67(5):1726–1736. doi: 10.1002/hep.29546. Epub 2018 Mar 23. PMID: 28941364; PMCID: PMC5866219.

Li J, Zou B, Yeo YH, Feng Y, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999–2019: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2019 May;4(5):389–398. doi: 10.1016/S2468–1253(19)30039–1. Epub 2019 Mar 20. PMID: 30902670.

Saokaew S, Kanchanasurakit S, Thawichai K, et al. Association of non-alcoholic fatty liver disease and allcause mortality in hospitalized cardiovascular disease patients: A systematic review and meta-analysis. Medicine (Baltimore). 2021 Feb 5;100(5): e24557. doi: 10.1097/ MD.0000000000024557. PMID: 33592910; PMCID: PMC7870191.

Драпкина О. М., Ивашкин В. Т. Рос журн гастроэнтерол, гепатол, колопроктол. – 2014. – Т. 24, № 4. – С. 32–38.

Drapkina O.M., Ivashkin V. T. Ros zhurn gastroenterol, hepatol, coloproctol. 2014;24(4):32–38 (in Russ.).

В. Т. Ивашкин, О. М. Драпкина Российсский журнал гастроэнтерологии, гепатологии, копрологии – 2015. – Т. 25. – № 6. – С. 31–38

Ivashkin V.T., Drapkina O. M. Russian Journal of Gastroenterology, Hepatology, Coprology. 2015; 25(6):31–38 (in Russ.).

Younossi ZM, Marchesini G, Pinto- Cortez H, Petta S. Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Implications for Liver Transplantation. Transplantation. 2019 Jan;103(1):22–27. doi: 10.1097/TP.0000000000002484. PMID: 30335697.

Lonardo A, Nascimbeni F, Ballestri S, Fairweather D, Win S, Than TA, Abdelmalek MF, Suzuki A. Sex Diff erences in Nonalcoholic Fatty Liver Disease: State of the Art and Identifi cation of Research Gaps. Hepatology. 2019 Oct;70(4):1457–1469. doi: 10.1002/hep.30626. Epub 2019 Sep 23. PMID: 30924946; PMCID: PMC6766425.

Anderson EL, Howe LD, Jones HE, Higgins JP, Lawlor DA, Fraser A. Th e Prevalence of Non- Alcoholic Fatty Liver Disease in Children and Adolescents: A Systematic Review and Meta- Analysis. PLoS One. 2015 Oct 29;10(10): e0140908. doi: 10.1371/journal.pone.0140908. PMID: 26512983; PMCID: PMC4626023.

Younes R, Bugianesi E. NASH in Lean Individuals. Semin Liver Dis. 2019 Feb;39(1):86–95. doi: 10.1055/s-0038– 1677517. Epub 2019 Jan 17. PMID: 30654392.

Qing Ye, Biyao Zou, Yee Hui Yeo, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. The Lancet Gastroenterology & Hepatology, Volume 5, Issue 8, 2020, Pages 739–752, ISSN 2468–1253, Doi: 10.1016/S2468–1253(20)30077–7.

Gentric G, Maillet V, Paradis V, et al. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest. 2015 Mar 2;125(3):981–92. doi: 10.1172/JCI73957. Epub 2015 Jan 26. PMID: 25621497; PMCID: PMC4362240.

Stine JG, Wentworth BJ, Zimmet A, Rinella ME, Loomba R, Caldwell SH, Argo CK. Systematic review with metaanalysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharmacol Th er. 2018 Oct;48(7):696 – 703. doi: 10.1111/apt.14937. Epub 2018 Aug 22. PMID: 30136293; PMCID: PMC7495494.

Wongjarupong N, Assavapongpaiboon B, Susantitaphong P, Cheungpasitporn W, Treeprasertsuk S, Rerknimitr R, Chaiteerakij R. Non-alcoholic fatty liver disease as a risk factor for cholangiocarcinoma: a systematic review and meta-analysis. BMC Gastroenterol. 2017 Dec 8;17(1):149. doi: 10.1186/s12876–017–0696–4. PMID: 29216833; PMCID: PMC5721586.

Lin X, You F, Liu H, Fang Y, Jin S, Wang Q. Site-specifi c risk of colorectal neoplasms in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis. PLoS One. 2021 Jan 25;16(1): e0245921. doi: 10.1371/journal. pone.0245921. PMID: 33493235; PMCID: PMC7833217.

Chen J, Bian D, Zang S, Yang Z, Tian G, Luo Y, Yang J, Xu B, Shi J. Th e association between nonalcoholic fatty liver disease and risk of colorectal adenoma and cancer incident and recurrence: a meta-analysis of observational studies. Expert Rev Gastroenterol Hepatol. 2019 Apr;13(4):385–395. doi: 10.1080/17474124.2019.1580143. Epub 2019 Feb

PMID: 30791768. 19. Chen W, Wang M, Jing X, Wu C, Zeng Y, Peng J, Cai X. High risk of colorectal polyps in men with non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2020 Dec;35(12):2051–2065. doi: 10.1111/jgh.15158. Epub 2020 Jul 7. PMID: 32579269.

Ballestri S, Zona S, Targher G, et al. 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. 2016 May;31(5):936–44. doi: 10.1111/jgh.13264. PMID: 26667191.

Fouad Y, Waked I, Bollipo S, Gomaa A, Ajlouni Y, Attia D. What’s in a name? Renaming ‘NAFLD’ to ‘MAFLD’. Liver Int. 2020 Jun;40(6):1254–1261. doi: 10.1111/liv.14478. Epub 2020 Apr 28. PMID: 32301554.

Eslam M, Newsome PN, Sarin SK, et al. A new defi nition for metabolic dysfunction- associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020 Jul;73(1):202–209. doi: 10.1016/j.jhep.2020.03.039. Epub 2020 Apr 8. PMID: 32278004.

Li L, Liu DW, Yan HY, Wang ZY, Zhao SH, Wang B. Obesity is an independent risk factor for non-alcoholic fatty liver disease: evidence from a meta-analysis of 21 cohort studies. Obes Rev. 2016 Jun;17(6):510–9. doi: 10.1111/obr.12407. Epub 2016 Mar 28. PMID: 27020692.

Jarvis H, Craig D, Barker R, Spiers G, Stow D, Anstee QM, Hanratty B. Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of populationbased observational studies. PLoS Med. 2020 Apr 30;17(4): e1003100. doi: 10.1371/journal.pmed.1003100. PMID: 32353039; PMCID: PMC7192386.

Loomis AK, Kabadi S, Preiss D, et al. Body Mass Index and Risk of Nonalcoholic Fatty Liver Disease: Two Electronic Health Record Prospective Studies. J Clin Endocrinol Metab. 2016 Mar;101(3):945–52. doi: 10.1210/jc.2015–3444. Epub 2015 Dec 16. PMID: 26672639; PMCID: PMC4803162.

van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, London R, Peduto T, Chisholm DJ, George J. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008 Aug;48(2):449–57. doi: 10.1002/hep.22350. PMID: 18627003.

Kim D, Chung GE, Kwak MS, Seo HB, Kang JH, Kim W, Kim YJ, Yoon JH, Lee HS, Kim CY. Body Fat Distribution and Risk of Incident and Regressed Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol. 2016 Jan;14(1):132–8.e4. doi: 10.1016/j.cgh.2015.07.024. Epub 2015 Jul 27. PMID: 26226099.

Lu FB, Hu ED, Xu LM, Chen L, Wu JL, Li H, Chen DZ, Chen YP. Th e relationship between obesity and the severity of non-alcoholic fatty liver disease: systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol. 2018 May;12(5):491–502. doi: 10.1080/17474124.2018.1460202. Epub 2018 Apr 2. PMID: 29609501.

Wu, S.J.; Zou, H.; Zhu, G.Q.; Wang, L.R.; Zhang, Q.; Shi, K.Q.; Han, J.B.; Huang, W.J.; Braddock, M.; Chen, Y.P., et al. Increased levels of systolic blood pressure within the normal range are associated with signifi cantly elevated risks of nonalcoholic fatty liver disease. Medicine (USA) 2015, 94.

Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired- biopsy studies. Clin Gastroenterol Hepatol. 2015 Apr;13(4):643–54.e1–9; quiz e39–40. doi: 10.1016/j.cgh.2014.04.014. Epub 2014 Apr 24. PMID: 24768810; PMCID: PMC4208976.

Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018 Jan;15(1):11–20. doi: 10.1038/nrgastro.2017.109. Epub 2017 Sep 20. PMID: 28930295.

Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: Clinical impact. J Hepatol. 2018 Feb;68(2):268–279. doi: 10.1016/j.jhep.2017.09.003. Epub 2017 Nov 6. PMID: 29122391.

Trépo E, Valenti L. Update on NAFLD genetics: From new variants to the clinic. J Hepatol. 2020 Jun;72(6):1196–1209. doi: 10.1016/j.jhep.2020.02.020. Epub 2020 Mar 4. PMID: 32145256.

Chen X, Zhou P, De L, Li B, Su S. Th e roles of transmembrane 6 superfamily member 2 rs58542926 polymorphism in chronic liver disease: A meta-analysis of 24,147 subjects. Mol Genet Genomic Med. 2019 Aug;7(8): e824. doi: 10.1002/mgg3.824. Epub 2019 Jul 15. PMID: 31309745; PMCID: PMC6687636.

Wang P, Wu CX, Li Y, Shen N. HSD17B13 rs72613567 protects against liver diseases and histological progression of nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2020 Sep;24(17):8997–9007. doi: 10.26355/eurrev_202009_22842. PMID: 32964989.

Barrera F, George J. Th e role of diet and nutritional intervention for the management of patients with NAFLD. Clin Liver Dis. 2014 Feb;18(1):91–112. doi: 10.1016/j. cld.2013.09.009. Epub 2013 Oct 24. PMID: 24274867.

Berná G, Romero- Gomez M. Th e role of nutrition in non-alcoholic fatty liver disease: Pathophysiology and management. Liver Int. 2020 Feb;40 Suppl 1:102–108. doi: 10.1111/liv.14360. PMID: 32077594.

Abdelmalek MF, Suzuki A, Guy C, Unalp- Arida A, Colvin R, Johnson RJ, Diehl AM; Nonalcoholic Steatohepatitis Clinical Research Network. Increased fructose consumption is associated with fi brosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010 Jun;51(6):1961–71. doi: 10.1002/hep.23535. PMID: 20301112; PMCID: PMC2922495.

Hannou SA, Haslam DE, McKeown NM, Herman MA. Fructose metabolism and metabolic disease. J Clin Invest. 2018 Feb 1;128(2):545–555. doi: 10.1172/JCI96702. Epub 2018 Feb 1. PMID: 29388924; PMCID: PMC5785258.

Soft ic S, Cohen DE, Kahn CR. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci. 2016 May;61(5):1282–93. doi: 10.1007/s10620– 016–4054–0. Epub 2016 Feb 8. PMID: 26856717; PMCID: PMC4838515.

Jensen T, Abdelmalek MF, Sullivan S, et al.. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018 May;68(5):1063–1075. doi: 10.1016/j. jhep.2018.01.019. Epub 2018 Feb 2. PMID: 29408694; PMCID: PMC5893377.

Zhao S, Jang C, Liu J, Uehara K, et al. Dietary fructose feeds hepatic lipogenesis via microbiota- derived acetate. Nature. 2020 Mar;579(7800):586–591. doi: 10.1038/ s41586–020–2101–7. Epub 2020 Mar 18. PMID: 32214246; PMCID: PMC7416516.

Liang JQ, Teoh N, Xu L, Pok S, Li X, Chu ESH, Chiu J, Dong L, Arfi anti E, Haigh WG, Yeh MM, Ioannou GN, Sung JJY, Farrell G, Yu J. Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling. Nat Commun. 2018 Oct 26;9(1):4490. doi: 10.1038/s41467–018–06931–6. PMID: 30367044; PMCID: PMC6203711.

Wang X, Cai B, Yang X, et al. Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metab. 2020 May 5;31(5):969–986.e7. doi: 10.1016/j.cmet.2020.03.010. Epub 2020 Apr 6. PMID: 32259482; PMCID: PMC7313619.

Ioannou GN, Morrow OB, Connole ML, Lee SP. Association between dietary nutrient composition and the incidence of cirrhosis or liver cancer in the United States population. Hepatology. 2009 Jul;50(1):175–84. doi: 10.1002/ hep.22941. PMID: 19441103.

Argo CK, Patrie JT, Lackner C, et al. Eff ects of n-3 fi sh oil on metabolic and histological parameters in NASH: a doubleblind, randomized, placebo- controlled trial. J Hepatol. 2015 Jan;62(1):190–7. doi: 10.1016/j.jhep.2014.08.036. Epub 2014 Sep 6. PMID: 25195547; PMCID: PMC4272639.

Yan JH, Guan BJ, Gao HY, Peng XE. Omega-3 polyunsaturated fatty acid supplementation and non-alcoholic fatty liver disease: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2018 Sep;97(37): e12271. doi: 10.1097/MD.0000000000012271. PMID: 30212963; PMCID: PMC6155966.

He XX, Wu XL, Chen RP, Chen C, Liu XG, Wu BJ, Huang ZM. Eff ectiveness of Omega-3 Polyunsaturated Fatty Acids in Non- Alcoholic Fatty Liver Disease: A MetaAnalysis of Randomized Controlled Trials. PLoS One. 2016 Oct 6;11(10): e0162368. doi: 10.1371/journal. pone.0162368. PMID: 27711128; PMCID: PMC5053538.

Martin PG, Guillou H, Lasserre F, Déjean S, Lan A, Pascussi JM, Sancristobal M, Legrand P, Besse P, Pineau T. Novel aspects of PPARalpha- mediated regulation of lipid and xenobiotic metabolism revealed through a nutrigenomic study. Hepatology. 2007 Mar;45(3):767–77. doi: 10.1002/hep.21510. PMID: 17326203.

Ducheix S, Montagner A, Polizzi A, et al. Essential fatty acids defi ciency promotes lipogenic gene expression and hepatic steatosis through the liver X receptor. J Hepatol. 2013 May;58(5):984–92. doi: 10.1016/j.jhep.2013.01.006. Epub 2013 Jan 16. PMID: 23333450.

Dentin R, Benhamed F, Pégorier JP, et al. Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation. J Clin Invest. 2005 Oct;115(10):2843–54. doi: 10.1172/ JCI25256. Epub 2005 Sep 22. PMID: 16184193; PMCID: PMC1224299.

Sekiya M, Yahagi N, Matsuzaka T, Najima Y, Nakakuki M, Nagai R, Ishibashi S, Osuga J, Yamada N, Shimano H. Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression. Hepatology. 2003 Dec;38(6):1529–39. doi: 10.1016/j.hep.2003.09.028. PMID: 14647064.

Lin J, Yang R, Tarr PT, et al.. Hyperlipidemic eff ects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell. 2005 Jan 28;120(2):261–73. doi: 10.1016/j.cell.2004.11.043. PMID: 15680331.

Desvergne B, Michalik L, Wahli W. Transcriptional regulation of metabolism. Physiol Rev. 2006 Apr;86(2):465–514. doi: 10.1152/physrev.00025.2005. PMID: 16601267.

Garcia- Caraballo SC, Comhair TM, Verheyen F, et al. Prevention and reversal of hepatic steatosis with a high-protein diet in mice. Biochim Biophys Acta. 2013 May;1832(5):685–95. doi: 10.1016/j.bbadis.2013.02.003. Epub 2013 Feb 11. PMID: 23410526.

Garcia Caraballo SC, Comhair TM, Houten SM, Dejong CH, Lamers WH, Koehler SE. High-protein diets prevent steatosis and induce hepatic accumulation of monomethyl branched- chain fatty acids. J Nutr Biochem. 2014 Dec;25(12):1263–74. doi: 10.1016/j.jnutbio.2014.07.005. Epub 2014 Sep 16. PMID: 25287814.

Schwarz J, Tomé D, Baars A, Hooiveld GJ, Müller M. Dietary protein aff ects gene expression and prevents lipid accumulation in the liver in mice. PLoS One. 2012;7(10): e47303. doi: 10.1371/journal.pone.0047303. Epub 2012 Oct 23. PMID: 23110065; PMCID: PMC3479095.

Gaggini M, Carli F, Rosso C, et al. Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance. Hepatology. 2018 Jan;67(1):145–158. doi: 10.1002/hep.29465. Epub 2017 Nov 17. PMID: 28802074.

Mardinoglu A, Agren R, Kampf C, Asplund A, Uhlen M, Nielsen J. Genome- scale metabolic modelling of hepatocytes reveals serine defi ciency in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:3083. doi: 10.1038/ncomms4083. PMID: 24419221.

Mardinoglu A, Bjornson E, Zhang C, et al. Personal modelassisted identifi cation of NAD+ and glutathione metabolism as intervention target in NAFLD. Mol Syst Biol. 2017 Mar 2;13(3):916. doi: 10.15252/msb.20167422. PMID: 28254760; PMCID: PMC5371732.

Lake AD, Novak P, Shipkova P, et al. Branched chain amino acid metabolism profi les in progressive human nonalcoholic fatty liver disease. Amino Acids. 2015 Mar;47(3):603– 15. doi: 10.1007/s00726–014–1894–9. Epub 2014 Dec 23. PMID: 25534430; PMCID: PMC4329055.

Hoyles L, Fernández- Real JM, Federici M, et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med. 2018 Jul;24(7):1070– 1080. doi: 10.1038/s41591–018–0061–3. Epub 2018 Jun 25. Erratum in: Nat Med. 2018 Aug 9;: PMID: 29942096; PMCID: PMC6140997.

Zhang F, Zhao S, Yan W, et al. Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy. EBioMedicine. 2016 Nov;13:157–167. doi: 10.1016/j.ebiom.2016.10.013. Epub 2016 Oct 11. PMID: 27843095; PMCID: PMC5264279.

Grzych G, Vonghia L, Bout MA, et al. Plasma BCAA Changes in Patients With NAFLD Are Sex Dependent. J Clin Endocrinol Metab. 2020 Jul 1;105(7): dgaa175. doi: 10.1210/clinem/dgaa175. PMID: 32271385.

Shoaie S, Ghaffari P, Kovatcheva- Datchary P, et al. Quantifying Diet- Induced Metabolic Changes of the Human Gut Microbiome. Cell Metab. 2015 Aug 4;22(2):320–31. doi: 10.1016/j.cmet.2015.07.001. PMID: 26244934.

Liu S, Liu Y, Wan B, et al. Association between Vitamin D Status and Non- Alcoholic Fatty Liver Disease: A Population- Based Study. J Nutr Sci Vitaminol (Tokyo). 2019;65(4):303–308. doi: 10.3177/jnsv.65.303. PMID: 31474679.

Mansour- Ghanaei F, Pourmasoumi M, Hadi A, Ramezani- Jolfaie N, Joukar F. Th e Effi cacy of Vitamin D Supplementation against Nonalcoholic Fatty Liver Disease: A Meta- Analysis. J Diet Suppl. 2020;17(4):467–485. doi: 10.1080/19390211.2019.1624671. Epub 2019 Jul 1. PMID: 31256692.

Nagashimada M, Ota T. Role of vitamin E in nonalcoholic fatty liver disease. IUBMB Life. 2019 Apr;71(4):516–522. doi: 10.1002/iub.1991. Epub 2018 Dec 27. PMID: 30592129.

Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander- Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010 May 6;362(18):1675–85. doi: 10.1056/NEJMoa0907929. Epub 2010 Apr 28. PMID: 20427778; PMCID: PMC2928471.

Xiao Zhang, Ting Gao, Senwen Deng, et al. Fasting induces hepatic lipid accumulation by stimulating peroxisomal dicarboxylic acid oxidation. Journal of Biological Chemistry, 2021, 296, 100622, Doi: 10.1016/j.jbc.2021.100622.

Martin, Timothy D, Dalhousie University. Faculty of Agriculture, and Kirsti Rouvinen- Watt. 2013. “Indicators of Infl ammation in the Fasting Induced Fatty Liver of the American Mink (Neovison Vison).” Dissertation. Dalhousie University.

Zhuang P, Shou Q, Wang W, He L, Wang J, Chen J, Zhang Y, Jiao J. Essential Fatty Acids Linoleic Acid and α- Linolenic Acid Sex- Dependently Regulate Glucose Homeostasis in Obesity. Mol Nutr Food Res. 2018 Sep;62(17): e1800448. doi: 10.1002/mnfr.201800448. Epub 2018 Aug 12. PMID: 29935107.

Zhang HJ, He J, Pan LL, et al. Eff ects of Moderate and Vigorous Exercise on Nonalcoholic Fatty Liver Disease: A Randomized Clinical Trial. JAMA Intern Med. 2016 Aug 1;176(8):1074–82. doi: 10.1001/jamainternmed.2016.3202. PMID: 27379904.

Buzzetti E, Linden A, Best LM, et al. Lifestyle modifi cations for nonalcohol- related fatty liver disease: a network meta-analysis. Cochrane Database Syst Rev. 2021 Jun 11;6(6): CD013156. doi: 10.1002/14651858.CD013156. pub2. PMID: 34114650; PMCID: PMC8193812.

Dajani AI, Popovic B. Essential phospholipids for nonalcoholic fatty liver disease associated with metabolic syndrome: A systematic review and network meta-analysis. World J Clin Cases. 2020 Nov 6;8(21):5235–5249. doi: 10.12998/wjcc.v8.i21.5235. PMID: 33269259; PMCID: PMC7674728.

Maev IV, Samsonov AA, Palgova LK, Pavlov CS, Vovk EI, Shirokova EN, Starostin KM. Eff ectiveness of phosphatidylcholine in alleviating steatosis in patients with non-alcoholic fatty liver disease and cardiometabolic comorbidities (MANPOWER study). BMJ Open Gastroenterol. 2020 Jan 13;7(1): e000341. doi: 10.1136/bmjgast-2019–000341. PMID: 32095253; PMCID: PMC7011021.

Dajani, A.I., Abuhammour, A. Agents for the treatment of fatty liver disease: focus on essential phospholipids. Drugs Th er Perspect 37, 249–264 (2021). Doi: 10.1007/ s40267–021–00838-x

The authors declare that there are no conflicts of interest present.