Avila, M.A. (Matías Antonio)

Berasain, C. (Carmen)

Dadun, University of Navarra

EDITORIALVitamin A in Nonalcoholic Fatty Liver Disease: A Key Player in anOffside Position?onalcoholic fatty liver disease (NAFLD) has becomeNthe most common liver disease at a global scale andis strongly associated with the obesity and metabolic syn-drome epidemic.1 NAFLD embodies a spectrum of liverconditions that may progress from an apparently benignaccumulation of lipids (steatosis) to inflammatory stagesaccompanied by hepatocellular damage known as nonalco-holic steatohepatitis (NASH). In a significant number ofpatients NASH progression can lead to cirrhosis and hepa-tocellular carcinoma development.2 In fact, NASH will soonsurpass alcoholic liver disease as the leading transplantindication for all patients.2 The clinical and socioeconomicburden of NAFLD has spurred extraordinary research ac-tivity on this disease.3 The mechanisms of NAFLD devel-opment appear complex and multifarious.4 A systemicdysregulation of energy metabolism characterized by excessdietary intake of fat and carbohydrates, insulin resistance,enhanced de novo hepatic lipogenesis, and increased hepa-tocyte uptake of fatty acids results in the hepatic accumu-lation of toxic lipids, hepatocellular death, and parenchymalinflammation.5 In addition, compromised expression andactivity of transcription factors such as liver X receptor,farnesoid X receptor, peroxisome proliferator-activated re-ceptors a and g, sterol response element binding protein-1c,and carbohydrate response element binding protein, keyregulators of lipid and glucose metabolism, are also involvedin NAFLD progression.6 Chronic parenchymal injury andinflammation trigger a potent tissue repair reaction domi-nated by the transdifferentiation of quiescent hepatic stel-late cells (HSCs) into extracellular matrix-producingmyofibroblasts, which drive liver fibrosis.4 Inflammationand fibrosis are key risk factors for liver disease progressionin NASH, and together with the transcription factorsmentioned above, they encompass major potential targetsfor NASH therapy.3,4Chronic liver diseases (CLD), including NAFLD, arecommonly associated with nutrient and vitamin deficienciessuch as those of vitamins D and A.7,8 In the broad context ofNAFLD pathogenesis, vitamin A sits at a critical crossroadbetween metabolic regulation and HSC activation and thusmay be regarded as a pivotal factor.9 Indeed, HSCs representthe principal systemic reserve of retinol. After passingthrough the hepatocytes, dietary retinol is mostly taken upand stored as retinyl-palmitate esters (RE) in lipid dropletscharacteristic of quiescent HSCs.10 In response to liverinjury HSCs become activated and rapidly loss their vitaminA contents in a process that has been mechanistically linkedto CLD progression and the onset of vitamin A deficiency(VAD).10 On the other hand, on conversion into retinoicacids (RA) vitamin A exerts potent systemic regulatoryCellulaeffects on many physiological processes including lipid andcarbohydrate metabolism. This is achieved through RAbinding to retinoid X receptor (RXR) and retinoid acid re-ceptor (RAR) transcription factors, which operate in director indirect coordination with the metabolic transcriptionfactors previously mentioned.8,9 Experimental and clinicalfindings indicate that normal RA signaling is important toprevent NAFLD,10 and that patients carrying the NAFLD riskvariant of patatin-like phospholipase domain-containingprotein 3 (PNPLA3-I148M) have low serum retinol concen-trations.11 Moreover, low serum and hepatic retinol levels,taken as indicators of VAD, have been observed in NAFLDpatients in association with disease progression.8 Thesefindings strongly suggest the presence of a pathogenic VADin NAFLD. However, the ultimate mechanisms determiningthe nature of this vitamin A inadequacy are not fully un-derstood. In this issue of Cellular and Molecular Gastroen-terology and Hepatology Saeed et al12 provide clarifyingexperimental insights into this matter that may be relevantfor patients’ management.The authors implement 2 complementary models ofNASH, mice fed with a high-fat and high-cholester-ol–containing diet and leptin-deficient ob/ob mouse. In bothmodels a reduction in hepatic retinol levels was confirmedin correlation with NASH progression, but most importantly,a significant increase in hepatic retinyl palmitate was found(Figure 1A). This is a relevant observation, because RE arethe most abundant form of vitamin A in the body, and theirhepatic accumulation would suggest that in spite of reducedserum retinol levels a true VAD does not occur in NASH.This finding seemed at variance with previous reports thatshowed a reduction in hepatic RE in NAFLD models andpatients.13,14 However, as the authors demonstrate,different experimental procedures for RE extraction fromlipid-laden liver tissue may account for such discrepancy.This observation raises a general note of caution for futurestudies addressing vitamin A metabolism in fatty livers.Another important finding of this work was the realizationthat hepatic accumulation of retinyl palmitate in NASH tookplace in hepatocytes, not in HSCs, which are their naturalcellular depot. This situation was attributed to the over-expression in hepatocytes of lecithin-retinol acyltransferase(Lrat), coding for the main enzyme in RE synthesis.Increased hepatic LRAT expression has been previously re-ported in NAFLD patients.15 However, Saeed et al12 providean interesting observation by showing that in primary he-patocytes (Figure 1B), but not in primary HSCs, Lratexpression can be induced by palmitate, and that retinyl-palmitate accumulated when cells were co-treated withretinol. Conversely, in HSCs, palmitate enhanced ther and Molecular Gastroenterology and Hepatology 2021;11:291–293Figure 1. Nonalcoholic fatty liver disease results in disturbed hepatic vitamin A metabolism. (A) Feeding a high-fat andhigh-cholesterol (HFC) diet, or leptin deficiency (ob/obmice), leads to reduced hepatic retinol levels and to the accumulation ofretinyl esters in mice. (B) Incubation of primary rat hepatocytes with palmitate results in up-regulation of expression of lecithin-retinol acyltransferase (Lrat), the main enzyme in retinyl ester synthesis normally expressed in hepatic stellate cells. Whenprimary rat hepatocytes are incubated with retinol and palmitate, retinyl palmitate is readily synthetized and accumulated.These responses contribute to understand the in vivo findings showing increased LRAT staining and vitamin A–laden auto-fluorescent vesicular structures found in parenchymal liver cells from HFC-fed mice.292 Berasain and Avila Cellular and Molecular Gastroenterology and Hepatology Vol. 11, No. 1expression of Pnpla3, which is endowed with RE hydrolaseactivity. The specific mechanisms underlying the differentialeffects of palmitate on Lrat and Pnpla3 expression in he-patocytes and HSCs still need to be worked out. Yet, thiswork contributes to explain the accumulation of vitamin Ain hepatocytes previously found in human fatty liver.16From a broader perspective, the study of Saeed et alwould also identify novel pathogenic mechanisms forpalmitate in NAFLD. The ectopic accumulation of retinylesters in hepatocytes and the overall dysregulation ofvitamin A metabolism, likely impacting on RAR/RXRsignaling networks, should now be added to the list of toxicstimuli mediated by this fatty acid.5,17 Although many as-pects of vitamin A metabolism in NAFLD remain to beclarified, this experimental report provides insightful in-formation that may help guide future NAFLD treatmentstrategies.CARMEN BERASAIN, PhDMATIAS A. AVILA, PhDHepatology Program, CIMAUniversity of NavarraPamplona, SpainNational Institute for the Study of Liver and GastrointestinalDiseases(CIBERehd, Carlos III Health Institute)Madrid, SpainIdiSNANavarra Institute for Health ResearchPamplona, SpainReferences1. Muthiah MD, Sanyal AJ. Burden of disease due tononalcoholic fatty liver disease. Gastroenterol Clin NorthAm 2020;49:1–23.2. Sheka AC, Adeyi O, Thompson J, et al. Nonalcoholicsteatohepatitis: a review. JAMA 2020;323:1175–1183.3. Byrne CD, Targher G. What’s new in NAFLD pathogen-esis, biomarkers and treatment? Nat Rev GastroenterolHepatol 2020;17:70–71.4. Friedman SL, Neuschwander-Tetri BA, Rinella M, et al.Mechanisms of NAFLD development and therapeuticstrategies. Nat Med 2018;24:908–922.5. Parthasarathy G, Revelo X, Malhi H. Pathogenesis ofnonalcoholic steatohepatitis: an overview. HepatolCommun 2020;4:478–492.6. Steensels S, Qiao J, Ersoy BA. Transcriptional regulationin non-alcoholic fatty liver disease. Metabolites 2020;10:283.7. Pacifico L, Osborn JF, Bonci E, et al. Association be-tween vitamin D levels and nonalcoholic fatty liver dis-ease: potential confounding variables. Mini-ReviewsMed Chem 2018;19:310–332.2021 Editorial 2938. Saeed A, Dullaart RPF, Schreuder TCMA, et al. Disturbedvitamin A metabolism in non-alcoholic fatty liver disease(NAFLD). Nutrients 2017;10:29.9. Blaner WS. Vitamin A signaling and homeostasis inobesity, diabetes, and metabolic disorders. PharmacolTher 2019;197:153–178.10. Haaker MW, Vaandrager AB, Helms JB. Retinoids inhealth and disease: a role for hepatic stellate cells inaffecting retinoid levels. Biochim Biophys Acta - Mol CellBiol Lipids 2020:1865.11. Kovarova M, Königsrainer I, Königsrainer A, et al. Thegenetic variant I148M in PNPLA3 is associated withincreased hepatic retinyl-palmitate storage in humans.J Clin Endocrinol Metab 2015;100:E1568–E1574.12. Saeed A, Bartuzi P, Heegsma J, et al. Impaired hepaticvitamin A metabolism in NAFLD mice leading to vitaminA accumulation in hepatocytes. Cell Mol GastroenterolHepatol 2021;11:309–325.13. Trasino SE, Tang XH, Jessurun J, et al. Obesity leadsto tissue, but not serum vitamin A deficiency. Sci Rep2015;5.14. Zhong G, Kirkwood J, Won KJ, et al. Characterization ofvitamin A metabolome in human livers with and withoutnonalcoholic fatty liver disease. J Pharmacol Exp Ther2019;370:92–103.15. Ashla AA, Hoshikawa Y, Tsuchiya H, et al. Geneticanalysis of expression profile involved in retinoidmetabolism in non-alcoholic fatty liver disease. HepatolRes 2010;40:594–604.16. Croce AC, Simone U De, Freitas I, et al. Human liverautofluorescence: an intrinsic tissue parameter discrim-inating normal and diseased conditions. Lasers SurgMed 2010;42:371–378.17. Hirsova P, Ibrabim SH, Gores GJ, et al. Thematic reviewseries: lipotoxicity—many roads to cell dysfunction andcell death lipotoxic lethal and sublethal stress signaling inhepatocytes: relevance to NASH pathogenesis. J LipidRes 2016;57:1758–1770.CorrespondenceAddress correspondence to: Matias A. Avila, BPharm, PhD, HepatologyProgram, CIMA, University of Navarra, Avda Pio XII, n55, 31008 Pamplona,Spain. e-mail: maavila@unav.es; fax: 34-948-194717.Conflicts of interestThe authors disclose no conflicts.FundingSupported by grants PI02019-104878RB-100 and PI02019-104265RB-100from FEDER/Ministerio de Ciencia, Innovación y Universidades-AgenciaEstatal de Investigación, and HEPACARE Project from Fundación La Caixa.Most current article© 2021 The Authors. Published by Elsevier Inc. on behalf of the AGAInstitute. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).2352-345Xhttps://doi.org/10.1016/j.jcmgh.2020.08.007

Vitamin A in nonalcoholic fatty liver disease: a key player in an offside position?

Universidad de Navarra

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Vitamin A in nonalcoholic fatty liver disease: a key player in an offside position?

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