{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T11:24:34Z","timestamp":1788002674644,"version":"build-2784847793"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:00:00Z","timestamp":1726617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013795","name":"Fujian Medical University","doi-asserted-by":"publisher","award":["2020QH1153 2022QH1346"],"award-info":[{"award-number":["2020QH1153 2022QH1346"]}],"id":[{"id":"10.13039\/501100013795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>There is limited research on cholesterol metabolism-related genes (CM-RGs) in non-alcoholic fatty liver disease (NAFLD), despite hypercholesterolemia being a recognized risk factor. The role of CM-RGs in NAFLD remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The differentially expressed genes (DEGs) between NAFLD and control were acquired by differential expression analysis. The differentially expressed genes associated with cholesterol metabolism (DE-CM-RGs) were identified and functional enrichment analyses were performed. Protein-protein interaction network analysis and a two-sample Mendelian randomization study were utilized for identifying hub genes. Nomogram model, competing endogenous RNA and messenger RNA-drug networks were established. In addition, immunoinfiltration analysis was performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified four hub genes (MVK, HMGCS1, TM7SF2, and FDPS) linked to NAFLD risk. MVK and TM7SF2 were protective factors, HMGCS1 and FDPS were risk factors for NAFLD. The area under the curve values of nomograms in GSE135251 and GSE126848 were 0.79 and 0.848, respectively. The gene set enrichment analysis indicated that hub genes participated in calcium signaling pathways and biosynthesis of unsaturated fatty acids. NAFLD patients showed increased CD56<jats:sup>dim<\/jats:sup> NK cells and Th17. Tretinoin, alendronate, zoledronic acid, and quercetin are potential target agents in NAFLD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study has linked cholesterol metabolism genes (MVK, HMGCS1, TM7SF2, and FDPS) to NAFLD, providing a promising diagnostic framework, identifying treatment targets, and offering novel perspectives into its mechanisms.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2024.1464865","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T05:03:08Z","timestamp":1726635788000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification of novel targets associated with cholesterol metabolism in nonalcoholic fatty liver disease: a comprehensive study using Mendelian randomization combined with transcriptome analysis"],"prefix":"10.3389","volume":"15","author":[{"given":"Juan","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajing","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.1080\/15384101.2016.1195939","article-title":"Impaired cell proliferation in regenerating liver of 3 \u03b2-hydroxysterol \u039414-reductase (TM7SF2) knock-out mice","volume":"15","author":"Bartoli","year":"2016","journal-title":"Cell Cycle"},{"key":"B2","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet. Epidemiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1002\/jimd.12412","article-title":"Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria","volume":"44","author":"Brennenstuhl","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1007\/s10654-015-0011-z","article-title":"Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors","volume":"30","author":"Burgess","year":"2015","journal-title":"Eur. J. Epidemiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"763538","DOI":"10.3389\/fendo.2021.763538","article-title":"Relationship between serum amino acid levels and bone mineral density: a mendelian randomization study","volume":"12","author":"Cui","year":"2021","journal-title":"Front. Endocrinol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e0230307","DOI":"10.1371\/journal.pone.0230307","article-title":"Characterization of the immune cell landscape of patients with NAFLD","volume":"15","author":"Diedrich","year":"2020","journal-title":"PloS one"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3464","DOI":"10.2337\/db14-1314","article-title":"Alterations of a cellular cholesterol metabolism network are a molecular feature of obesity-related type 2 diabetes and cardiovascular disease","volume":"64","author":"Ding","year":"2015","journal-title":"Diabetes"},{"key":"B9","doi-asserted-by":"publisher","first-page":"33649","DOI":"10.18632\/oncotarget.9259","article-title":"IL-33 treatment attenuated diet-induced hepatic steatosis but aggravated hepatic fibrosis","volume":"7","author":"Gao","year":"2016","journal-title":"Oncotarget"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e0141885","DOI":"10.1371\/journal.pone.0141885","article-title":"The Tm7sf2 gene deficiency protects mice against endotoxin-induced acute kidney injury","volume":"10","author":"Gatticchi","year":"2015","journal-title":"PloS one"},{"key":"B11","doi-asserted-by":"publisher","first-page":"592573","DOI":"10.3389\/fcell.2020.592573","article-title":"Tm7sf2 disruption alters radial gene positioning in mouse liver leading to metabolic defects and diabetes characteristics","volume":"8","author":"Gatticchi","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"118897","DOI":"10.1016\/j.bbamcr.2020.118897","article-title":"Tm7sf2 gene promotes adipocyte differentiation of mouse embryonic fibroblasts and improves insulin sensitivity","volume":"1868","author":"Gatticchi","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1007\/s11427-016-9027-6","article-title":"Retinoic acid ameliorates high-fat diet-induced liver steatosis through sirt1","volume":"60","author":"Geng","year":"2017","journal-title":"Sci. China Life Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/1750-1172-1-13","article-title":"Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome","volume":"1","author":"Haas","year":"2006","journal-title":"Orphanet J. Rare Dis."},{"key":"B15","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinforma."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s12865-017-0215-y","article-title":"The imbalance of Th17\/Treg cells is involved in the progression of nonalcoholic fatty liver disease in mice","volume":"18","author":"He","year":"2017","journal-title":"BMC Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"eLife"},{"key":"B19","doi-asserted-by":"publisher","first-page":"13","DOI":"10.4137\/CIN.S13495","article-title":"OmicCircos: a simple-to-use R package for the circular visualization of multidimensional omics data","volume":"13","author":"Hu","year":"2014","journal-title":"Cancer Inf."},{"key":"B20","doi-asserted-by":"publisher","first-page":"751436","DOI":"10.3389\/fnut.2021.751436","article-title":"Integrated transcriptomic and translatomic inquiry of the role of betaine on lipid metabolic dysregulation induced by a high-fat diet","volume":"8","author":"Huang","year":"2021","journal-title":"Front. Nutr."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1007\/s10875-011-9571-1","article-title":"Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis","volume":"31","author":"Inzaugarat","year":"2011","journal-title":"J. Clin. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.tem.2015.11.008","article-title":"The role of cholesterol in the pathogenesis of NASH","volume":"27","author":"Ioannou","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"B23","doi-asserted-by":"publisher","first-page":"686","DOI":"10.3945\/ajcn.2009.27738","article-title":"Novel variants at KCTD10, MVK, and MMAB genes interact with dietary carbohydrates to modulate HDL-cholesterol concentrations in the genetics of lipid lowering drugs and diet network study","volume":"90","author":"Junyent","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e2306827","DOI":"10.1002\/advs.202306827","article-title":"CSN6-SPOP-HMGCS1 Axis promotes hepatocellular carcinoma progression via YAP1 activation","volume":"11","author":"Li","year":"2024","journal-title":"Adv. Sci. (Weinh)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"4490","DOI":"10.1038\/s41467-018-06931-6","article-title":"Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling","volume":"9","author":"Liang","year":"2018","journal-title":"Nat. Commun."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e23035","DOI":"10.1096\/fj.202300433RR","article-title":"Farnesyl diphosphate synthase exacerbates nonalcoholic steatohepatitis via the activation of AHR-CD36 axis","volume":"37","author":"Liu","year":"2023","journal-title":"FASEB J."},{"key":"B27","doi-asserted-by":"publisher","first-page":"130","DOI":"10.3945\/ajcn.114.105155","article-title":"Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease","volume":"102","author":"Liu","year":"2015","journal-title":"Am. J. Clin. Nutr."},{"key":"B28","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/j.ajhg.2017.01.026","article-title":"The genetic architecture of gene expression in peripheral blood","volume":"100","author":"Lloyd-Jones","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"154233","DOI":"10.1016\/j.phymed.2022.154233","article-title":"Ursolic acid inhibits the cholesterol biosynthesis and alleviates high fat diet-induced hypercholesterolemia via irreversible inhibition of HMGCS1 in vivo","volume":"103","author":"Ma","year":"2022","journal-title":"Phytomedicine"},{"key":"B31","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.jhep.2017.11.014","article-title":"Lipotoxicity and the gut-liver axis in NASH pathogenesis","volume":"68","author":"Marra","year":"2018","journal-title":"J. Hepatology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"172469","DOI":"10.1016\/j.ejphar.2019.172469","article-title":"Zoledronic acid prevents the hepatic changes associated with high fat diet in rats; the potential role of mevalonic acid pathway in nonalcoholic steatohepatitis","volume":"858","author":"Mohamed","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1093\/nutrit\/nuy022","article-title":"Systematic review and meta-analysis of controlled intervention studies on the effectiveness of long-chain omega-3 fatty acids in patients with nonalcoholic fatty liver disease","volume":"76","author":"Musa-Veloso","year":"2018","journal-title":"Nutr. Rev."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1016\/j.clnu.2017.08.031","article-title":"Omega-3 PUFA modulate lipogenesis, ER stress, and mitochondrial dysfunction markers in NASH - proteomic and lipidomic insight","volume":"37","author":"Okada","year":"2018","journal-title":"Clin. Nutr."},{"key":"B35","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1016\/j.cmet.2016.10.012","article-title":"Physiological suppression of lipotoxic liver damage by complementary actions of HDAC3 and SCAP\/SREBP","volume":"24","author":"Papazyan","year":"2016","journal-title":"Cell Metab."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1125415","DOI":"10.3389\/fimmu.2023.1125415","article-title":"Systemic lupus erythematosus is causally associated with hypothyroidism, but not hyperthyroidism: a Mendelian randomization study","volume":"14","author":"Qin","year":"2023","journal-title":"Front. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"97","DOI":"10.4049\/jimmunol.1501175","article-title":"Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17\/resting regulatory T cell ratio in peripheral blood and in the liver","volume":"196","author":"Rau","year":"2016","journal-title":"J. Immunol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"101133","DOI":"10.1016\/j.aohep.2023.101133","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"29","author":"Rinella","year":"2024","journal-title":"Ann. hepatology"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1797","DOI":"10.1097\/HEP.0000000000000323","article-title":"AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease","volume":"77","author":"Rinella","year":"2023","journal-title":"Hepatology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/1471-2105-12-77","article-title":"pROC: an open-source package for R and S+ to analyze and compare ROC curves","volume":"12","author":"Robin","year":"2011","journal-title":"BMC Bioinforma."},{"key":"B41","doi-asserted-by":"publisher","first-page":"6207","DOI":"10.1210\/jc.2019-00160","article-title":"Overeating saturated fat promotes fatty liver and ceramides compared with polyunsaturated fat: a randomized trial","volume":"104","author":"Rosqvist","year":"2019","journal-title":"J. Clin. Endocrinol. metabolism"},{"key":"B42","doi-asserted-by":"publisher","first-page":"5265","DOI":"10.1038\/s41388-019-0791-9","article-title":"FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases\/AKT axis","volume":"38","author":"Seshacharyulu","year":"2019","journal-title":"Oncogene"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1778","DOI":"10.1002\/hep.32589","article-title":"PAR2 promotes impaired glucose uptake and insulin resistance in NAFLD through GLUT2 and Akt interference","volume":"76","author":"Shearer","year":"2022","journal-title":"Hepatology"},{"key":"B44","doi-asserted-by":"publisher","first-page":"293","DOI":"10.3389\/fimmu.2017.00293","article-title":"Role of distinct natural killer cell subsets in anticancer response","volume":"8","author":"Stabile","year":"2017","journal-title":"Front. Immunol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"4402","DOI":"10.1016\/j.csbj.2022.07.030","article-title":"Establishment and validation of a cholesterol metabolism-related prognostic signature for hepatocellular carcinoma","volume":"20","author":"Tang","year":"2022","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1053\/j.gastro.2011.06.040","article-title":"Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis","volume":"141","author":"Van Rooyen","year":"2011","journal-title":"Gastroenterology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1002\/path.5789","article-title":"Cardiac-specific deletion of FDPS induces cardiac remodeling and dysfunction by enhancing the activity of small GTP-binding proteins","volume":"255","author":"Wang","year":"2021","journal-title":"J. Pathology"},{"key":"B48","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innov. Camb. (Mass)"},{"key":"B49","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1186\/s12916-023-02878-8","article-title":"Oxidative stress gene expression, DNA methylation, and gut microbiota interaction trigger Crohn's disease: a multi-omics Mendelian randomization study","volume":"21","author":"Xu","year":"2023","journal-title":"BMC Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"3140","DOI":"10.1002\/ptr.6486","article-title":"Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db\/db mice","volume":"33","author":"Yang","year":"2019","journal-title":"Phytother. Res."},{"key":"B51","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatol. Baltim. Md"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"B53","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics a J. Integr. Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"115323","DOI":"10.1016\/j.biopha.2023.115323","article-title":"Ligustilide covalently binds to Cys129 of HMGCS1 to ameliorate dyslipidemia","volume":"166","author":"Zhang","year":"2023","journal-title":"Biomed. and Pharmacother. = Biomedecine and Pharmacother."},{"key":"B55","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1136\/gutjnl-2019-319664","article-title":"Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites","volume":"70","author":"Zhang","year":"2021","journal-title":"Gut"},{"key":"B56","doi-asserted-by":"publisher","first-page":"F662","DOI":"10.1152\/ajprenal.00046.2008","article-title":"Expression profiling of hepatic genes associated with lipid metabolism in nephrotic rats","volume":"295","author":"Zhou","year":"2008","journal-title":"Am. J. Physiol. Ren. Physiol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1464865\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T05:03:10Z","timestamp":1726635790000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1464865\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,18]]},"references-count":56,"alternative-id":["10.3389\/fgene.2024.1464865"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2024.1464865","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,18]]},"article-number":"1464865"}}