{"doi":"10.15252/embj.2021109997","title":"Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut","abstract":"Lysosome-mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that, unexpectedly, feeding activates intestinal autophagy/lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the gut hormone, fibroblast growth factor-15/19 (FGF15/19). Furthermore, postprandial intestinal triglycerides (TGs) and apolipoprotein-B48 (ApoB48), the TG-rich chylomicron marker, were elevated in SHP-knockout and FGF15-knockout mice. Genomic analyses of the mouse intestine indicated that SHP partners with the key lysosomal activator, transcription factor-EB (TFEB) to upregulate the transcription of autophagy/lipolysis network genes after feeding. FGF19 treatment activated lipophagy, reducing TG and ApoB48 levels in HT29 intestinal cells, which was dependent on TFEB. Mechanistically, feeding-induced FGF15/19 signaling increased the nuclear localization of TFEB and SHP via PKC beta/zeta-mediated phosphorylation, leading to increased transcription of the TFEB/SHP target lipophagy genes, Ulk1 and Atgl. Collectively, these results demonstrate that paradoxically after feeding, FGF15/19-activated SHP and TFEB activate gut lipophagy, limiting postprandial TGs. As excess postprandial lipids cause dyslipidemia and obesity, the FGF15/19-SHP-TFEB axis that reduces intestinal TGs via lipophagic activation provides promising therapeutic targets for obesity-associated metabolic disease.","journal":"The EMBO Journal","year":2022,"id":256469,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":244425,"name":"Young‐Chae Kim","orcid":"0000-0002-5130-4413","position":1,"is_corresponding":false},{"id":51372,"name":"Yang Zhang","orcid":"0000-0002-1483-9195","position":2,"is_corresponding":false},{"id":305847,"name":"Bo Kong","orcid":"0000-0002-8200-7817","position":3,"is_corresponding":false},{"id":246449,"name":"Grace L. Guo","orcid":"0000-0002-2666-0635","position":4,"is_corresponding":false},{"id":51348,"name":"Jian Ma","orcid":"0000-0002-4202-5834","position":5,"is_corresponding":false},{"id":248079,"name":"Byron Kemper","orcid":null,"position":6,"is_corresponding":false},{"id":244428,"name":"Jongsook Kim Kemper","orcid":"0000-0002-5534-0286","position":7,"is_corresponding":false},{"id":248078,"name":"Sunmi Seok","orcid":null,"position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T00:25:25.728895Z","pmid":"35686465","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":[]}