{"doi":"10.1073/pnas.2318619121","title":"The fatty liver disease–causing protein PNPLA3-I148M alters lipid droplet–Golgi dynamics","abstract":", encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD. Despite its discovery 20 y ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-driven cellular change.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":429722,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9639,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":561028,"name":"Lei Liu","orcid":"0000-0001-6290-8602","position":1,"is_corresponding":false},{"id":1163394,"name":"Jennifer L. Mamrosh","orcid":"0000-0003-1391-2706","position":2,"is_corresponding":false},{"id":595179,"name":"Jiansong Xie","orcid":null,"position":3,"is_corresponding":false},{"id":1163395,"name":"John Ferbas","orcid":"0000-0003-4087-4629","position":4,"is_corresponding":false},{"id":469736,"name":"Brett Lomenick","orcid":"0000-0002-5023-9998","position":5,"is_corresponding":false},{"id":228766,"name":"Mark S. Ladinsky","orcid":"0000-0002-1036-3513","position":6,"is_corresponding":false},{"id":1163396,"name":"Rati Verma","orcid":"0009-0002-9885-0144","position":7,"is_corresponding":false},{"id":1163397,"name":"Ingrid C. Rulifson","orcid":"0000-0003-3251-3989","position":8,"is_corresponding":false},{"id":604686,"name":"Raymond J. Deshaies","orcid":"0000-0002-3671-9354","position":9,"is_corresponding":false},{"id":1163392,"name":"David J. Sherman","orcid":"0000-0002-2120-0971","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T01:59:11.328802Z","pmid":"38657050","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}