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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 \u2013 WNT\/\u03b2\u2010Catenin, Hedgehog, HIPPO\/Yap\/TAZ and Notch \u2013 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\u2010specific activation of these pathways may explain the variability in clinical presentation, and the zone\u2010specific response observed in clinical trials.<\/jats:p>","DOI":"10.1111\/liv.15025","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T15:36:40Z","timestamp":1627659400000},"page":"2534-2546","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Zonation in NASH \u2013 A key paradigm for understanding pathophysiology and clinical outcomes"],"prefix":"10.1111","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9492-4746","authenticated-orcid":false,"given":"Jonathan B.","family":"Steinman","sequence":"first","affiliation":[{"name":"Department of Pediatrics Columbia University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela 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