{"doi":"10.1172/jci.insight.147692","title":"Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1","abstract":"Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than 1000 nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here, we show that histone demethylase LSD1 KO from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD+ synthesis and limits NAD+ availability in the nucleus. Lsd1 KO reduces NAD+-dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPβ and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in the liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.","journal":"JCI Insight","year":2021,"id":188522,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":749647,"name":"Lingyi Tang","orcid":"0000-0002-4804-7241","position":1,"is_corresponding":false},{"id":749648,"name":"Kang Du","orcid":"0009-0007-5333-0627","position":2,"is_corresponding":false},{"id":398243,"name":"Kitt Paraiso","orcid":"0000-0002-6489-810X","position":3,"is_corresponding":false},{"id":232989,"name":"Qiushi Sun","orcid":"0000-0002-0296-2612","position":4,"is_corresponding":false},{"id":749649,"name":"Zhengxia Liu","orcid":"0000-0001-7394-0480","position":5,"is_corresponding":false},{"id":749650,"name":"Xiaolong Ye","orcid":"0000-0002-6975-0294","position":6,"is_corresponding":false},{"id":619327,"name":"Yuan Fang","orcid":"0000-0003-0483-2237","position":7,"is_corresponding":false},{"id":578542,"name":"Fang Yuan","orcid":"0000-0002-4050-7362","position":8,"is_corresponding":false},{"id":749651,"name":"Hank Chen","orcid":"0000-0003-0504-1592","position":9,"is_corresponding":false},{"id":459922,"name":"Yumay Chen","orcid":"0000-0001-7985-0654","position":10,"is_corresponding":false},{"id":749652,"name":"Xiaorong Wang","orcid":"0000-0002-1912-3890","position":11,"is_corresponding":false},{"id":289624,"name":"Clinton Yu","orcid":"0000-0002-2931-5474","position":12,"is_corresponding":false},{"id":398244,"name":"Ira L. 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