{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:20:32Z","timestamp":1790659232348,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["GR-2019-12370172"],"award-info":[{"award-number":["GR-2019-12370172"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF-2021-12374481"],"award-info":[{"award-number":["RF-2021-12374481"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["PNRR-MCNT2-2023-12378295"],"award-info":[{"award-number":["PNRR-MCNT2-2023-12378295"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetics strongly impacts the course of metabolic dysfunction-associated steatotic liver disease (MASLD), with the I148M Patatin like phospholipase domain containing 3 (PNPLA3) variant representing the main modifier. Fat accumulation in the hepatic lobule, strongly enhanced by this SNP, may be influenced by the liver\u2019s zonation. Therefore, we applied spatial transcriptomics to investigate the metabolic processes across portal (PZ)-central (CZ) zones in I148M PNPLA3 carriers. Visium CytAssist technology was applied to liver biopsies from MASLD patients sharing similar disease severity, who were wild-type (WT) or homozygous for the I148M variant (Discovery cohort, n = 4). The distribution of steatosis, inflammation, and fibrosis was assessed in the liver biopsies of MASLD patients, stratified according to the I148M variant (validation cohort, n = 100). At the Visium-LOUPE browser, we spatially mapped PZ and CZ hepatocytes (HEPs), revealing higher lipid turnover, glucose signaling, and lower mitochondrial activity in I148M-PZ-HEPs compared to 148M-CZ-HEPs. Thus, the I148M variant could unbalance the physiological hepatic zonation boosting steatosis development in PZ, consequently inducing mitochondrial dysfunction. The unsupervised analysis confirmed the altered metabolic pattern among CZ and PZ in patients carrying the variant. Interestingly, PNPLA3 expression was higher in I148M-PZ, which also showed an enrichment of non-parenchymal cells, thus possibly explaining the more severe injury in this area. Finally, in the validation cohort, we observed a pronounced PZ distribution of steatosis, inflammation, and fibrosis in I148M PNPLA3 subjects compared to WT, confirming the spatial data. The I148M variant contributes to the metabolic switching across different hepatic zones and represents a new clinical perspective by defining a specific histological pattern of MASLD.<\/jats:p>","DOI":"10.3390\/ijms27031601","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T10:05:47Z","timestamp":1770372347000},"page":"1601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The I148M PNPLA3 Variant Forces Progressive Portal MASLD by Spatially Perturbing Metabolic Pathways Across Liver Zones"],"prefix":"10.3390","volume":"27","author":[{"given":"Erika","family":"Paolini","sequence":"first","affiliation":[{"name":"Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4161-4178","authenticated-orcid":false,"given":"Marica","family":"Meroni","sequence":"additional","affiliation":[{"name":"Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9433-3492","authenticated-orcid":false,"given":"Miriam","family":"Longo","sequence":"additional","affiliation":[{"name":"Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Badiali","sequence":"additional","affiliation":[{"name":"Department of Surgery, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Maggioni","sequence":"additional","affiliation":[{"name":"Department of Pathology, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5918-0171","authenticated-orcid":false,"given":"Anna Ludovica","family":"Fracanzani","sequence":"additional","affiliation":[{"name":"Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4343-7213","authenticated-orcid":false,"given":"Paola","family":"Dongiovanni","sequence":"additional","affiliation":[{"name":"Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver, European Association for the Study of Diabetes, and European Association for the Study of Obesity (2024). 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