{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T16:27:57Z","timestamp":1784305677624,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T00:00:00Z","timestamp":1660780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DK107735"],"award-info":[{"award-number":["R01 DK107735"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Choline deficiency causes hepatic fat accumulation, and is associated with a higher risk of nonalcoholic fatty liver disease (NAFLD) and more advanced NAFLD-related hepatic fibrosis. Reduced expression of hepatic phosphatidylethanolamine N-methyltransferase (PEMT), which catalyzes the production of phosphatidylcholine, causes steatosis, inflammation, and fibrosis in mice. In humans, common PEMT variants impair phosphatidylcholine synthesis, and are associated with NAFLD risk. We investigated hepatic PEMT expression in a large cohort of patients representing the spectrum of NAFLD, and examined the relationship between PEMT genetic variants and gene expression. Hepatic PEMT expression was reduced in NAFLD patients with inflammation and fibrosis (i.e., nonalcoholic steatohepatitis or NASH) compared to participants with normal liver histology (\u03b2 = \u22121.497; p = 0.005). PEMT levels also declined with increasing severity of fibrosis with cirrhosis &lt; incomplete cirrhosis &lt; bridging fibrosis (\u03b2 = \u22121.185; p = 0.011). Hepatic PEMT expression was reduced in postmenopausal women with NASH compared to those with normal liver histology (\u03b2 = \u22123.698; p = 0.030). We detected a suggestive association between rs7946 and hepatic fibrosis (p = 0.083). Although none of the tested variants were associated with hepatic PEMT expression, computational fine mapping analysis indicated that rs4646385 may impact PEMT levels in the liver. Hepatic PEMT expression decreases with increasing severity of NAFLD in obese individuals and postmenopausal women, and may contribute to disease pathogenesis in a subset of NASH patients.<\/jats:p>","DOI":"10.3390\/ijms23169296","type":"journal-article","created":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T21:39:21Z","timestamp":1660858761000},"page":"9296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Hepatic PEMT Expression Decreases with Increasing NAFLD Severity"],"prefix":"10.3390","volume":"23","author":[{"given":"Ignazio S.","family":"Piras","sequence":"first","affiliation":[{"name":"Translational Genomics Research Institute, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anish","family":"Raju","sequence":"additional","affiliation":[{"name":"Translational Genomics Research Institute, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3316-6069","authenticated-orcid":false,"given":"Janith","family":"Don","sequence":"additional","affiliation":[{"name":"Translational Genomics Research Institute, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Schork","sequence":"additional","affiliation":[{"name":"Translational Genomics Research Institute, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6276-0337","authenticated-orcid":false,"given":"Glenn S.","family":"Gerhard","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3286-0270","authenticated-orcid":false,"given":"Johanna K.","family":"DiStefano","sequence":"additional","affiliation":[{"name":"Translational Genomics Research Institute, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2784537","DOI":"10.1155\/2018\/2784537","article-title":"Nonalcoholic Fatty Liver Disease Cirrhosis: A Review of Its Epidemiology, Risk Factors, Clinical Presentation, Diagnosis, Management, and Prognosis","volume":"2018","author":"Li","year":"2018","journal-title":"Can. J. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.cld.2004.04.004","article-title":"The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease","volume":"8","author":"McCullough","year":"2004","journal-title":"Clin. Liver Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Pennisi, G., Celsa, C., Giammanco, A., Spatola, F., and Petta, S. (2019). The Burden of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: Screening Issue and Future Perspectives. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225613"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1096\/fasebj.5.7.2010061","article-title":"Choline, an essential nutrient for humans","volume":"5","author":"Zeisel","year":"1991","journal-title":"FASEB J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.3945\/jn.114.197533","article-title":"Higher Dietary Choline Intake Is Associated with Lower Risk of Nonalcoholic Fatty Liver in Normal-Weight Chinese Women","volume":"144","author":"Yu","year":"2014","journal-title":"J. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4344","DOI":"10.1038\/s41598-018-22691-1","article-title":"Nutritionally recommended food for semi- to strict vegetarian diets based on large-scale nutrient composition data","volume":"8","author":"Kim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1097\/NT.0000000000000302","article-title":"Choline: The Underconsumed and Underappreciated Essential Nutrient","volume":"53","author":"Wallace","year":"2018","journal-title":"Nutr. Today"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"892","DOI":"10.3945\/ajcn.111.020156","article-title":"Choline intake in a large cohort of patients with nonalcoholic fatty liver disease","volume":"95","author":"Guerrerio","year":"2012","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.3945\/ajcn.2010.30064","article-title":"Dietary choline requirements of women: Effects of estrogen and genetic variation","volume":"92","author":"Fischer","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1093\/ajcn\/85.5.1275","article-title":"Sex and menopausal status influence human dietary requirements for the nutrient choline","volume":"85","author":"Fischer","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16025","DOI":"10.1073\/pnas.0504285102","article-title":"Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans","volume":"102","author":"Kohlmeier","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/iep.12008","article-title":"An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis","volume":"94","author":"Matsumoto","year":"2013","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"42358","DOI":"10.1074\/jbc.M204542200","article-title":"An Unexpected Requirement for Phosphatidylethanolamine N-Methyltransferase in the Secretion of Very Low Density Lipoproteins","volume":"277","author":"Noga","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"21721","DOI":"10.1038\/srep21721","article-title":"Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis","volume":"6","author":"Nakatsuka","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1042\/bj20021523","article-title":"Phosphatidylethanolamine N-methyltransferase (PEMT) knockout mice have hepatic steatosis and abnormal hepatic choline metabolite concentrations despite ingesting a recommended dietary intake of choline","volume":"370","author":"Zhu","year":"2003","journal-title":"Biochem. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1093\/jn\/132.1.68","article-title":"Choline deficiency-induced liver damage is reversible in Pemt(-\/-) mice","volume":"132","author":"Waite","year":"2002","journal-title":"J. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.bbalip.2012.07.017","article-title":"Physiological roles of phosphatidylethanolamine N-methyltransferase","volume":"1831","author":"Vance","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"22403","DOI":"10.1074\/jbc.M110.108514","article-title":"Impaired de Novo Choline Synthesis Explains Why Phosphatidylethanolamine N-Methyltransferase-deficient Mice Are Protected from Diet-induced Obesity","volume":"285","author":"Jacobs","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10986","DOI":"10.1096\/fj.201900679R","article-title":"Hepatic PEMT activity mediates liver health, weight gain, and insulin resistance","volume":"33","author":"Wan","year":"2019","journal-title":"FASEB J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1096\/fj.04-3580com","article-title":"Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD)","volume":"19","author":"Song","year":"2005","journal-title":"FASEB J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.jceh.2019.02.001","article-title":"Whole-Exome Sequencing Identifies a Variant in Phosphatidylethanolamine N-Methyltransferase Gene to be Associated With Lean-Nonalcoholic Fatty Liver Disease","volume":"9","author":"Bale","year":"2019","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2970","DOI":"10.1096\/fj.14-249557","article-title":"Identification of new genetic polymorphisms that alter the dietary requirement for choline and vary in their distribution across ethnic and racial groups","volume":"28","author":"Corbin","year":"2014","journal-title":"FASEB J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1074\/jbc.M110.106922","article-title":"Aberrant Estrogen Regulation of PEMT Results in Choline Deficiency-associated Liver Dysfunction","volume":"286","author":"Resseguie","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2622","DOI":"10.1096\/fj.07-8227com","article-title":"Phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes","volume":"21","author":"Resseguie","year":"2007","journal-title":"FASEB J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2998","DOI":"10.1016\/S0021-9258(18)69166-5","article-title":"The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes","volume":"263","author":"Yao","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1139\/o90-079","article-title":"Reduction in VLDL, but not HDL, in plasma of rats deficient in choline","volume":"68","author":"Yao","year":"1990","journal-title":"Biochem. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1093\/carcin\/16.2.327","article-title":"Effects of prolonged (1 year) choline deficiency and subsequent re-feeding of choline on 1,2-sn-diradylglycerol, fatty acids and protein kinase C in rat liver","volume":"16","author":"Garner","year":"1995","journal-title":"Carcinogenesis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12880","DOI":"10.1073\/pnas.94.24.12880","article-title":"Disruption of the murine gene encoding phosphatidylethanolamine N-methyltransferase","volume":"94","author":"Walkey","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1136\/bmj.2.4635.1001","article-title":"Liver damage produced by feeding alcohol or sugar and its prevention by choline","volume":"2","author":"Best","year":"1949","journal-title":"Br. Med. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1177\/0148607101025005260","article-title":"Choline Deficiency Causes Reversible Hepatic Abnormalities in Patients Receiving Parenteral Nutrition: Proof of a Human Choline Requirement: A Placebo-Controlled Trial","volume":"25","author":"Buchman","year":"2001","journal-title":"J. Parenter. Enter. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.jhep.2006.12.012","article-title":"The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population","volume":"46","author":"Dong","year":"2007","journal-title":"J. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1096\/fj.06-1005ufm","article-title":"People with fatty liver are more likely to have the PEMT rs7946 SNP, yet populations with the mutant allele do not have fatty liver","volume":"20","author":"Zeisel","year":"2006","journal-title":"FASEB J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1146\/annurev.nutr.26.061505.111156","article-title":"Choline: Critical Role During Fetal Development and Dietary Requirements in Adults","volume":"26","author":"Zeisel","year":"2006","journal-title":"Annu. Rev. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s00592-014-0654-3","article-title":"Genome-wide analysis of hepatic lipid content in extreme obesity","volume":"52","author":"DiStefano","year":"2015","journal-title":"Acta Diabetol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wood, G.C., Chu, X., Manney, C., Strodel, W., Petrick, A., Gabrielsen, J., Seiler, J., Carey, D., Argyropoulos, G., and Benotti, P. (2012). An electronic health record-enabled obesity database. BMC Med. Inform. Decis. Mak., 12.","DOI":"10.1186\/1472-6947-12-45"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"R25","DOI":"10.1186\/gb-2009-10-3-r25","article-title":"Ultrafast and memory-efficient alignment of short DNA sequences to the human genome","volume":"10","author":"Langmead","year":"2009","journal-title":"Genome Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2014A Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1186\/gb-2014-15-2-r29","article-title":"Voom: Precision weights unlock linear model analysis tools for RNA-seq read counts","volume":"15","author":"Law","year":"2014","journal-title":"Genome Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","article-title":"Adjusting batch effects in microarray expression data using empirical Bayes methods","volume":"8","author":"Johnson","year":"2007","journal-title":"Biostatistics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1001\/jama.2017.18261","article-title":"Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: US Preventive Services Task Force Recommendation Statement","volume":"318","author":"Grossman","year":"2017","journal-title":"JAMA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The Genotype-Tissue Expression (GTEx) project","volume":"45","author":"Consortium","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"1000 Genomes Project Consortium, Auton, A., Brooks, L.D., Durbin, R.M., Garrison, E.P., Kang, H.M., Korbel, J.O., Marchini, J.L., McCarthy, S., and McVean, G.A. (2015). A global reference for human genetic variation. Nature, 526, 68\u201374.","DOI":"10.1038\/nature15393"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1093\/bioinformatics\/btw615","article-title":"Improved methods for multi-trait fine mapping of pleiotropic risk loci","volume":"33","author":"Kichaev","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kichaev, G., Yang, W.-Y., Lindstrom, S., Hormozdiari, F., Eskin, E., Price, A.L., Kraft, P., and Pasaniuc, B. (2014). Integrating Functional Data to Prioritize Causal Variants in Statistical Fine-Mapping Studies. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004722"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9296\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:11:35Z","timestamp":1760141495000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9296"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,18]]},"references-count":44,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23169296"],"URL":"https:\/\/doi.org\/10.3390\/ijms23169296","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,18]]}}}