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Genetic variants of patatin\u2010like phospholipase domain containing 3 (\n                      <jats:italic>PNPLA3<\/jats:italic>\n                      ) are associated with MASLD susceptibility and statin treatment efficacy. Access to liver biopsies before established MASLD is limited, and statins and PNPLA3 in early liver steatosis are thus difficult to study.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Liver biopsies were collected from 261 patients without known liver disease at surgery and stratified based on statin use and criteria for the metabolic syndrome (MS). Genotypes and transcript levels were measured using Illumina and Affymetrix arrays, and metabolic and lipoprotein profiles by clinical assays. Statin effects on PNPLA3, de novo lipogenesis (DNL), and lipid accumulation were further studied in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The PNPLA3\n                      <jats:sup>I148M<\/jats:sup>\n                      genetic variant was associated with significantly lower hepatic levels of cholesterol synthesis\u2010associated transcripts. Patients with MS had significantly higher hepatic levels of MASLD and lipogenesis\u2010associated transcripts than non\u2010MS patients. Patients with MS on statin therapy had significantly higher hepatic levels of\n                      <jats:italic>PNPLA3<\/jats:italic>\n                      , acetyl\u2010CoA carboxylase alpha, and ATP citrate lyase, and statin use was associated with higher plasma fasting glucose, insulin, and HbA1c. Exposure of hepatocyte\u2010like HepG2 cells to atorvastatin promoted intracellular accumulation of triglycerides and lipogenesis\u2010associated transcripts. Atorvastatin\u2010exposure of HepG2, sterol\n                      <jats:italic>O<\/jats:italic>\n                      \u2010acyltransferase\n                      <jats:italic>(SOAT) 2<\/jats:italic>\n                      \u2010only\u2010HepG2, primary human hepatic stellate, and hepatic stellate cell\u2010like LX2 cells significantly increased levels of\n                      <jats:italic>PNPLA3<\/jats:italic>\n                      and SREBF2\u2010target genes, whereas knockdown of SREBF2 attenuated this effect.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Collectively, these observations suggest statin\u2010associated regulation of PNPLA3 and DNL in liver. The potential interaction between\n                      <jats:italic>PNPLA3<\/jats:italic>\n                      genotype and metabolic status should be considered in future studies in the context of statin therapy for MASLD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/joim.20032","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T08:40:08Z","timestamp":1732005608000},"page":"47-59","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Statin\u2010associated regulation of hepatic\n                    <i>PNPLA3<\/i>\n                    in patients without known liver disease"],"prefix":"10.1111","volume":"297","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2854-2552","authenticated-orcid":false,"given":"Osman","family":"Ahmed","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Center for Molecular Medicine, 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