{"doi":"10.1194/jlr.ra119000336","title":"Hepatic PLIN5 signals via SIRT1 to promote autophagy and prevent inflammation during fasting","abstract":"Lipid droplets (LDs) are energy-storage organelles that are coated with hundreds of proteins, including members of the perilipin (PLIN) family. PLIN5 is highly expressed in oxidative tissues, including the liver, and is thought to play a key role in uncoupling LD accumulation from lipotoxicity; however, the mechanisms behind this action are incompletely defined. We investigated the role of hepatic PLIN5 in inflammation and lipotoxicity in a murine model under both fasting and refeeding conditions and in hepatocyte cultures. PLIN5 ablation with antisense oligonucleotides triggered a pro-inflammatory response in livers from mice only under fasting conditions. Similarly, PLIN5 mitigated lipopolysaccharide- or palmitic acid-induced inflammatory responses in hepatocytes. During fasting, PLIN5 was also required for the induction of autophagy, which contributed to its anti-inflammatory effects. The ability of PLIN5 to promote autophagy and prevent inflammation were dependent upon signaling through sirtuin 1 (SIRT1), which is known to be activated in response to nuclear PLIN5 under fasting conditions. Taken together, these data show that PLIN5 signals via SIRT1 to promote autophagy and prevent FA-induced inflammation as a means to maintain hepatocyte homeostasis during periods of fasting and FA mobilization. Lipid droplets (LDs) are energy-storage organelles that are coated with hundreds of proteins, including members of the perilipin (PLIN) family. PLIN5 is highly expressed in oxidative tissues, including the liver, and is thought to play a key role in uncoupling LD accumulation from lipotoxicity; however, the mechanisms behind this action are incompletely defined. We investigated the role of hepatic PLIN5 in inflammation and lipotoxicity in a murine model under both fasting and refeeding conditions and in hepatocyte cultures. PLIN5 ablation with antisense oligonucleotides triggered a pro-inflammatory response in livers from mice only under fasting conditions. Similarly, PLIN5 mitigated lipopolysaccharide- or palmitic acid-induced inflammatory responses in hepatocytes. During fasting, PLIN5 was also required for the induction of autophagy, which contributed to its anti-inflammatory effects. The ability of PLIN5 to promote autophagy and prevent inflammation were dependent upon signaling through sirtuin 1 (SIRT1), which is known to be activated in response to nuclear PLIN5 under fasting conditions. Taken together, these data show that PLIN5 signals via SIRT1 to promote autophagy and prevent FA-induced inflammation as a means to maintain hepatocyte homeostasis during periods of fasting and FA mobilization. Intracellular lipid droplets (LDs) are energy-storage organelles composed of a core of neutral lipids surrounded by a phospholipid monolayer embedded with hundreds of proteins. LD accumulation in non-adipose tissue is tightly linked to numerous metabolic diseases, including type 2 diabetes (1Greenberg A.S. Coleman R.A. Kraemer F.B. McManaman J.L. Obin M.S. Puri V. Yan Q.W. Miyoshi H. Mashek D.G. The role of lipid droplets in metabolic disease in rodents and humans.J. Clin. Invest. 2011; 121: 2102-2110Crossref PubMed Scopus (456) Google Scholar), and is the defining characteristic of nonalcoholic fatty liver disease (NAFLD) (2Mashek D.G. Khan S.A. Sathyanarayan A. Ploeger J.M. Franklin M.P. Hepatic lipid droplet biology: getting to the root of fatty liver.Hepatology. 2015; 62: 964-967Crossref PubMed Scopus (80) Google Scholar). While LDs themselves are often considered inert, a growing body of literature shows that dysregulation of lipid metabolic pathways leading to the accumulation of intermediates in triacylglycerol (TAG) metabolism can trigger lipotoxicity and impair cellular homeostasis. In addition, the presence of specific proteins on the surface of LDs can couple/uncouple LD accumulation and cellular dysfunction. Perilipins (PLINs) are a family of constitutive LD proteins comprised of five members. PLIN2 is the most abundant is","journal":"Journal of Lipid Research","year":2020,"id":65582,"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":56,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":347321,"name":"Wenqi Cui","orcid":"0000-0003-2022-6050","position":1,"is_corresponding":false},{"id":347322,"name":"Michael Lopresti","orcid":"0000-0002-3656-4962","position":2,"is_corresponding":false},{"id":349282,"name":"Mara T. Mashek","orcid":null,"position":3,"is_corresponding":false},{"id":347323,"name":"Charles P. Najt","orcid":"0000-0001-6455-8810","position":4,"is_corresponding":false},{"id":347324,"name":"Hongbo Hu","orcid":"0000-0002-2780-5568","position":5,"is_corresponding":false},{"id":242842,"name":"Douglas G. Mashek","orcid":"0000-0001-7033-3386","position":6,"is_corresponding":false},{"id":347320,"name":"Enxiang Zhang","orcid":"0000-0002-1713-2523","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-18T21:13:43.728351Z","pmid":"31932301","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":[]}