CoChat
Sign Up
Cited by 49Liver Disease Diagnosis and TreatmentLiver physiology and pathologyLiver Diseases and Immunity

Zonation in NASH – A key paradigm for understanding pathophysiology and clinical outcomes

Open access
Steinman, Jonathan B., Salomao, Marcela A., Pajvani, Utpal B.·2021·Liver International
DOI 10.1111/liv.15025
Open this paper in CoChat — free accountOpen PDF

Abstract

Non‐alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance – WNT/β‐Catenin, Hedgehog, HIPPO/Yap/TAZ and Notch – have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient‐specific activation of these pathways may explain the variability in clinical presentation, and the zone‐specific response observed in clinical trials.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1111/liv.15025

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In zone 3, there is a well-known histologic pattern of liver damage in diseases that culminate in HCC, and zone 3 is frequently associated with oxidative stress.

    “In zone 3, there is a well-known histologic pattern of liver damage in diseases that culminate in HCC (61, 62), and zone 3 is frequently associated with oxidative stress (63, 64).”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [61]

    The Figure 2 caption shows a pericentral histologic pattern of NASH, but the copy does not link that pattern to HCC. More decisively, §4.2.1 (Vitamin E) places the highest oxidative stress in the periportal region, not zone 3; §4.3 likewise describes greater oxidative stress in the periportal area. Page numbers were not available in our copy. (LLM, conf=0.83)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Liver zonation is perturbed in CLD, including MASLD.

    “Accordingly, liver zonation is perturbed in CLD, including MASLD54,55.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [54]

    Section 1.2.1 (Immune response) says NAFLD exaggerates the liver’s periportal immune-cell pattern, supporting perturbed zonation in the disease the paper calls NAFLD. Section 2 (Developmental pathways as determinants of NAFLD zonation) also describes altered zonal distribution of signals in NAFLD/NASH. The paper does not establish the broader claim for chronic liver disease generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 85

  1. Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and out- comes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5:739-752.
  2. Eslam M, Fan J-G, Mendez-Sanchez N. Non-alcoholic fatty liver disease in non-obese individuals: the impact of metabolic health. Lancet Gastroenterol Hepatol. 2020;5:713-715.
  3. Eslam M, Sanyal AJ, George J, International Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020;158:1999- 2014.e1.
  4. Benedict M, Zhang X. Non-alcoholic fatty liver disease: an ex- panded review. World J Hepatol. 2017;9:715-732.
  5. Mishra A, Younossi ZM. Epidemiology and natural history of non- alcoholic fatty liver disease. J Clin Exp Hepatol. 2012;2:135-144.
  6. D'Avola D, Labgaa I, Villanueva A. Natural history of nonalcoholic steatohepatitis/nonalcoholic fatty liver disease-hepatocellular carcinoma: magnitude of the problem from a hepatology clinic perspective. Clin Liver Dis. 2016;8:100-104.
  7. Lindenmeyer CC, McCullough AJ. The natural history of non- alcoholic fatty liver disease -an evolving view. Clin Liver Dis. 2018;22:11-21.
  8. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389-97.e10.
  9. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53:1874-1882.
  10. Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865-873.
  11. Younossi ZM. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: implications for liver transplantation. Liver Transpl. 2018;24:166-170.
  12. Sayiner M, Younossi ZM. Nonalcoholic steatohepatitis is becoming a top indication for liver transplantation worldwide. Liver Transpl. 2019;25:10-11.
  13. Neuschwander-Tetri BA. Therapeutic landscape for NAFLD in 2020. Gastroenterology. 2020;158:1984-1998.e3.
  14. Younossi ZM, Loomba R, Rinella ME, et al. Current and future ther- apeutic regimens for nonalcoholic fatty liver disease and nonalco- holic steatohepatitis. Hepatology. 2018;68:361-371.
  15. Gordillo M, Evans T, Gouon-Evans V. Orchestrating liver develop- ment. Development. 2015;142:2094-2108.
  16. Ober EA, Lemaigre FP. Development of the liver: insights into organ and tissue morphogenesis. J Hepatol. 2018;68:1049-1062.
  17. Jungermann K, Kietzmann T. Zonation of parenchymal and nonpa- renchymal metabolism in liver. Annu Rev Nutr. 1996;16:179-203.
  18. Ben-Moshe S, Itzkovitz S. Spatial heterogeneity in the mammalian liver. Nat Rev Gastroenterol Hepatol. 2019;16:395-410.
  19. Xiong X, Kuang H, Liu T, Lin JD. A single-cell perspective of the mam- malian liver in health and disease. Hepatology. 2020;71:1467-1473.
  20. Freitas-Lopes MA, Mafra K, David BA, Carvalho-Gontijo R, Menezes GB. Differential location and distribution of hepatic im- mune cells. Cells. 2017;6:48.
  21. Robinson MW, Harmon C, O'Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol. 2016;13:267-276.
  22. Gola A, Dorrington MG, Speranza E, et al. Commensal-driven immune zonation of the liver promotes host defence. Nature. 2021;589:131-136.
  23. Gadd VL, Skoien R, Powell EE, et al. The portal inflammatory infil- trate and ductular reaction in human nonalcoholic fatty liver dis- ease. Hepatology. 2014;59:1393-1405.
  24. Remmerie A, Martens L, Thoné T, et al. Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver. Immunity. 2020;53:641-657.e14.
  25. Ramachandran P, Dobie R, Wilson-Kanamori JR, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature. 2019;575:512-518.
  26. Richardson MM, Jonsson JR, Powell EE, et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regenera- tion and a ductular reaction. Gastroenterology. 2007;133:80-90.
  27. Skoien R, Richardson MM, Jonsson JR, et al. Heterogeneity of fibro- sis patterns in non-alcoholic fatty liver disease supports the pres- ence of multiple fibrogenic pathways. Liver Int. 2013;33:624-632.
  28. Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42:641-649.
  29. Carter-Kent C, Yerian LM, Brunt EM, et al. Nonalcoholic steato- hepatitis in children: a multicenter clinicopathological study. Hepatology. 2009;50:1113-1120.
  30. Takahashi Y, Inui A, Fujisawa T, Takikawa H, Fukusato T. Histopathological characteristics of non-alcoholic fatty liver disease in children: comparison with adult cases. Hepatol Res. 2011;41:1066-1074.
  31. Patton HM, Yates K, Unalp-Arida A, et al. Association between met- abolic syndrome and liver histology among children with nonalco- holic fatty liver disease. Am J Gastroenterol. 2010;105:2093-2102.
  32. Mann JP, Vito RD, Mosca A, et al. Portal inflammation is in- dependently associated with fibrosis and metabolic syn- drome in pediatric nonalcoholic fatty liver disease. Hepatology. 2016;63:745-753.
  33. Brunt EM, Kleiner DE, Wilson LA, et al. Portal chronic inflamma- tion in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-clinicopathologic correlations from the non- alcoholic steatohepatitis clinical research network. Hepatology. 2009;49:809-820.
  34. Africa JA, Behling CA, Brunt EM, et al. In children with nonalco- holic fatty liver disease, zone 1 steatosis is associated with ad- vanced fibrosis. Clin Gastroenterol Hepatol. 2018;16:438-446.e1.
  35. Alisi A, Bedogni G, De Vito R, Comparcola D, Manco M, Nobili V. Relationship between portal chronic inflammation and disease se- verity in paediatric non-alcoholic fatty liver disease. Dig Liver Dis. 2011;43:143-146.
  36. Valenti L, Alisi A, Galmozzi E, et al. I148M patatin-like phospholi- pase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology. 2010;52:1274-1280.
  37. Xanthakos SA, Lavine JE, Yates KP, et al. Progression of fatty liver disease in children receiving standard of care lifestyle advice. Gastroenterology. 2020;159:1731-1751.e10
  38. Simon TG, Roelstraete B, Hartjes K, et al. Non-alcoholic fatty liver disease in children and young adults is associated with increased long-term mortality. J Hepatol. 2021. doi:https://doi.org/10.1016/j. jhep.2021.06.034 · DOI
  39. Bedossa P. Histological assessment of NAFLD. Dig Dis Sci. 2016;61:1348-1355.
  40. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313-1321.
  41. Rakha EA, Adamson L, Bell E, et al. Portal inflammation is asso- ciated with advanced histological changes in alcoholic and non- alcoholic fatty liver disease. J Clin Pathol. 2010;63:790-795.
  42. Kanwar P, Nelson JE, Yates K, et al. Association between metabolic syndrome and liver histology among NAFLD patients without dia- betes. BMJ Open Gastroenterol. 2016;3:e000114.
  43. Yilmaz Y, Senates E, Yesil A, Ergelen R, Colak Y. Not only type 2 diabetes but also prediabetes is associated with portal inflamma- tion and fibrosis in patients with non-alcoholic fatty liver disease. J Diabetes Complications. 2014;28:328-331.
  44. Cast AE, Walter TJ, Huppert SS. Vascular patterning sets the stage for macro and micro hepatic architecture. Dev Dyn. 2015;244:497-506.
  45. Huppert SS, Iwafuchi-Doi M. Molecular regulation of mammalian hepatic architecture. Curr Top Dev Biol. 2019;132:91-136.
  46. Jungermann K, Katz N. Functional specialization of different he- patocyte populations. Physiol Rev. 1989;69:708-764.
  47. Machado MV, Diehl AM. Hedgehog signalling in liver pathophysi- ology. J Hepatol. 2018;68:550-562.
  48. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagno- sis and management. Eur J Hum Genet. 2012;20:251-257.
  49. Halpern KB, Shenhav R, Matcovitch-Natan O, et al. Single-cell spa- tial reconstruction reveals global division of labour in the mamma- lian liver. Nature. 2017;542:352-356.
  50. Behari J, Li H, Liu S, et al. β-catenin links hepatic metabolic zona- tion with lipid metabolism and diet-induced obesity in mice. Am J Pathol. 2014;184:3284-3298.
  51. Soto-Gutierrez A, Gough A, Vernetti LA, Taylor DL, Monga SP. Pre-clinical and clinical investigations of metabolic zonation in liver diseases: the potential of microphysiology systems. Exp Biol Med. 2017;242:1605-1616.
  52. Tao J, Xu E, Zhao Y, et al. Modeling a human hepatocellular car- cinoma subset in mice through coexpression of met and point- mutant β-catenin. Hepatology. 2016;64:1587-1605.
  53. Rebouissou S, Franconi A, Calderaro J, et al. Genotype-phenotype correlation of CTNNB1 mutations reveals different ß-catenin activity associated with liver tumor progression. Hepatology. 2016;64:2047-2061.
  54. Zhu C, Ho YJ, Salomao MA, et al. Notch activity characterizes a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features. J Hepatol. 2021;74:613-626.
  55. Verdelho Machado M, Diehl AM. The hedgehog pathway in nonalcoholic fatty liver disease. Crit Rev Biochem Mol Biol. 2018;53:264-278.
  56. Guy CD, Suzuki A, Zdanowicz M, et al. Hedgehog pathway acti- vation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 2012;55:1711-1721.
  57. Omenetti A, Bass LM, Anders RA, et al. Hedgehog activity, epithelial-mesenchymal transitions, and biliary dysmorphogenesis in biliary atresia. Hepatology. 2011;53:1246-1258.
  58. Swiderska-Syn M, Suzuki A, Guy CD, et al. Hedgehog path- way and pediatric nonalcoholic fatty liver disease. Hepatology. 2013;57:1814-1825.
  59. Anakk S, Bhosale M, Schmidt VA, Johnson RL, Finegold MJ, Moore DD. Bile acids activate YAP to promote liver carcinogenesis. Cell Rep. 2013;5:1060-1069.
  60. Mooring M, Fowl BH, Lum SZC, et al. Hepatocyte stress increases expression of yes-associated protein and transcriptional coactiva- tor with PDZ-binding motif in hepatocytes to promote parenchy- mal inflammation and fibrosis. Hepatology. 2020;71:1813-1830.
  61. Wang X, Zheng Z, Caviglia JM, et al. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepati- tis. Cell Metab. 2016;24:848-862.
  62. Wang X, Cai B, Yang X, et al. Cholesterol stabilizes TAZ in hepato- cytes to promote experimental non-alcoholic steatohepatitis. Cell Metab. 2020;31:969-986.e7.
  63. Sato K, Marzioni M, Meng F, et al. Ductular reaction in liver dis- eases: pathological mechanisms and translational significances. Hepatology. 2019;69:420-430.
  64. Bi P, Kuang S. Notch signaling as a novel regulator of metabolism. Trends Endocrinol Metab. 2015;26:248-255.
  65. Valenti L, Mendoza RM, Rametta R, et al. Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver dis- ease. Diabetes. 2013;62:4052-4062.
  66. Boulter L, et al. Macrophage-derived Wnt opposes notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012;18:572-579.
  67. Kahles F, Findeisen HM, Bruemmer D. Osteopontin: a novel regu- lator at the cross roads of inflammation, obesity and diabetes. Mol Metab. 2014;3:384-393.
  68. Gross B, Pawlak M, Lefebvre P, Staels B. PPARs in obesity- induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol. 2017;13:36-49.
  69. Tanaka N, Aoyama T, Kimura S, Gonzalez FJ. Targeting nuclear re- ceptors for the treatment of fatty liver disease. Pharmacol Ther. 2017;179:142-157.
  70. Kowalik MA, Columbano A, Perra A. Thyroid hormones, thyro- mimetics and their metabolites in the treatment of liver disease. Front Endocrinol. 2018;9:382.
  71. Chi HC, Chen C-Y, Tsai M-M, Tsai C-Y, Lin K-H. Molecular functions of thyroid hormones and their clinical significance in liver-related diseases. Biomed Res Int. 2013;2013:601361.
  72. Park SR, Cho C-S, Xi J, Kang HM, Lee JH. Holistic characterization of single-hepatocyte transcriptome responses to high-fat diet. Am J Physiol Endocrinol Metab. 2021;320:E244-E258.
  73. Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the big bang. Cell. 2014;157:255-266.
  74. Brosch M, Kattler K, Herrmann A, et al. Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control. Nat Commun. 2018;9:4150.
  75. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non- alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956-965.
  76. Liu X, Zhang X, Ji L, et al. Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma. Oncotarget. 2015;6:4226-4238.
  77. Thompson MD, Moghe A, Cornuet P, et al. β-catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis. Hepatology. 2018;67:955-971.
  78. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vita- min E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675-1685.
  79. Guy CD, Suzuki A, Abdelmalek MF, et al. Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity. Hepatology. 2015;61:98-107.
  80. Reimer KC, Wree A, Roderburg C, Tacke F. New drugs for NAFLD: lessons from basic models to the clinic. Hepatol Int. 2020;14: 8-23.
  81. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008-1017.
  82. Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol. 2013;10:676-685.
  83. Vallée A, Lecarpentier Y. Crosstalk between peroxisome proliferator-activated receptor gamma and the canonical WNT/β- catenin pathway in chronic inflammation and oxidative stress during carcinogenesis. Front Immunol. 2018;9:745.
  84. Moldes M, Zuo Y, Morrison RF, et al. Peroxisome-proliferator- activated receptor γ suppresses Wnt/β-catenin signalling during adipogenesis. Biochem J. 2003;376:607-613.
  85. Sharma C, Pradeep A, Wong L, Rana A, Rana B. Peroxisome proliferator-activated receptor gamma activation can regu- late beta-catenin levels via a proteasome-mediated and ade- nomatous polyposis coli-independent pathway. J Biol Chem. 2004;279:35583-35594.

Cited by

Sorted by citations

Authors
Steinman, J. B., Salomao, M. A., & Pajvani, U. B.
Affiliations
  • Columbia University (US)
  • Mayo Clinic (US)
Corresponding author
Pajvani, Utpal B.
ORCID
Venue
Liver International
Publisher
Wiley
Published
2021-08-18
Volume
41
Issue
11
Pages
2534-2546
ISSN
  • 0106-9543 (ISSN-L)
  • 1478-3223
  • 1478-3231
DOI
10.1111/liv.15025
OpenAlex
W3186275497
Cited by
49
References
14
Citations by year
2026: 10 · 2025: 12 · 2024: 15 · 2023: 5 · 2022: 4 · 2021: 3
FWCI
1.03
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Liver International (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
nonalcoholic steatohepatitis, hepatic zonation, liver fibrosis, Wnt/β-catenin signaling, Hedgehog signaling, Notch signaling, nuclear receptors, cysteamine, obeticholic acid, pioglitazone, treatment response variability, steatosis
MeSH terms
Pioglitazone, Humans, Liver, Liver Cirrhosis, Hepatocytes, Non-alcoholic Fatty Liver Disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review