{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T04:03:04Z","timestamp":1779163384167,"version":"3.51.4"},"reference-count":92,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Metabolic dysfunction-associated steatotic liver disease (MASLD) is estimated to affect \u223c30% of adults globally. The progressive form of MASLD, metabolic dysfunction-associated steatohepatitis (MASH), is a leading cause of chronic liver disease. MASH is marked by hepatocellular fat accumulation (steatosis), ballooning, and inflammation. Although many\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      models replicate MASH pathophysiology, no\n                      <jats:italic>in vitro<\/jats:italic>\n                      hepatocyte MASH model has been evaluated for its ability to reflect clinically observed changes in drug metabolizing enzymes (DMEs) and transporters. In this study, we addressed this gap by developing a model using sandwich-cultured human hepatocytes (SCHH) that mimics both MASH pathophysiology and alterations in DME and transporter concentrations and function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Lipid\u2013cytokine treatments were first optimized using differentiated HuH-7 cells based on cellular toxicity and their ability to induce a MASH-like phenotype. Three final treatments\u2014all including TNF-\u03b1 (1\u00a0ng\/mL) and IL-6 (1.2\u00a0ng\/mL)\u2014were selected for SCHH evaluation: (1) oleic acid (OA):palmitic acid (PA) (1:2, 0.5\u00a0mM), (2) a lipid mix (lysophospholipids mixture + OA:PA), and (3) lipid mix + 0.01\u00a0mM cholesterol. Treatments were incubated for 72\u00a0h with SCHH from three donors. Quantitative targeted absolute proteomics (QTAP) assessed the transporter and DME concentrations, whereas B-CLEAR\n                      <jats:sup>\u00ae<\/jats:sup>\n                      technology evaluated transporter function using the probe substrates [\n                      <jats:sup>3<\/jats:sup>\n                      H]-taurocholate (TCA) and [\n                      <jats:sup>3<\/jats:sup>\n                      H]-estradiol-17\u03b2-glucuronide (E\n                      <jats:sub>2<\/jats:sub>\n                      17G).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All three treatments significantly increased lipid droplet formation and peroxidation in SCHH with minimal toxicity. These treatments also altered DME and transporter concentrations in a manner similar to the changes observed in liver tissue from patients with MASH. Across treatments, concentrations of the bile salt export pump (BSEP), sodium taurocholate co-transporting polypeptide (NTCP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and multidrug resistance-associated protein (MRP) 2 were reduced by 0.66\u20130.57-fold, 0.71\u20130.52-fold, 0.74\u20130.63-fold, 0.82\u20130.80-fold, and 0.71\u20130.48-fold, respectively. Correspondingly, the TCA apparent uptake clearance and biliary clearance were reduced by 0.70\u20130.26-fold and 0.61\u20130.27-fold, respectively. E\n                      <jats:sub>2<\/jats:sub>\n                      17G apparent uptake clearance was reduced by 0.67\u20130.35-fold, whereas biliary excretion index values were reduced to negligible levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings demonstrate that lipid\u2013cytokine treatments induce MASH-like changes in SCHH, including clinically relevant reductions in DME and transporter concentrations and function. This model may serve as a valuable tool for predicting altered hepatobiliary drug disposition in MASH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1664808","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T08:12:00Z","timestamp":1768205520000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Development of an in vitro metabolic dysfunction-associated steatohepatitis model to investigate altered drug metabolizing enzymes, transport proteins, and hepatobiliary disposition"],"prefix":"10.3389","volume":"16","author":[{"given":"William A.","family":"Murphy","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarina","family":"Kyburz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Ho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew Shane","family":"Loop","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John K.","family":"Fallon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline B.","family":"Tiley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Kralj","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim L. 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