{"doi":"10.1016/j.jbc.2021.101104","title":"Glucose-mediated de novo lipogenesis in photoreceptors drives early diabetic retinopathy","abstract":"Diabetic retinopathy (DR) is an increasingly frequent cause of blindness across populations; however, the events that initiate pathophysiology of DR remain elusive. Strong preclinical and clinical evidence suggests that abnormalities in retinal lipid metabolism caused by diabetes may account for the origin of this disease. A major arm of lipid metabolism, de novo biosynthesis, is driven by elevation in available glucose, a common thread binding all forms of vision loss in diabetes. Therefore, we hypothesized that aberrant retinal lipid biogenesis is an important promoter of early DR. In murine models, we observed elevations of diabetes-associated retinal de novo lipogenesis ∼70% over control levels. This shift was primarily because of activation of fatty acid synthase (FAS), a rate-limiting enzyme in the biogenic pathway. Activation of FAS was driven by canonical glucose-mediated disinhibition of acetyl-CoA carboxylase, a major upstream regulatory enzyme. Mutant mice expressing gain-of-function FAS demonstrated increased vulnerability to DR, whereas those with FAS deletion in rod photoreceptors maintained preserved visual responses upon induction of diabetes. Excess retinal de novo lipogenesis—either because of diabetes or because of FAS gain of function—was associated with modestly increased levels of palmitate-containing phosphatidylcholine species in synaptic membranes, a finding with as yet uncertain significance. These findings implicate glucose-dependent increases in photoreceptor de novo lipogenesis in the early pathogenesis of DR, although the mechanism of deleterious action of this pathway remains unclear. Diabetic retinopathy (DR) is an increasingly frequent cause of blindness across populations; however, the events that initiate pathophysiology of DR remain elusive. Strong preclinical and clinical evidence suggests that abnormalities in retinal lipid metabolism caused by diabetes may account for the origin of this disease. A major arm of lipid metabolism, de novo biosynthesis, is driven by elevation in available glucose, a common thread binding all forms of vision loss in diabetes. Therefore, we hypothesized that aberrant retinal lipid biogenesis is an important promoter of early DR. In murine models, we observed elevations of diabetes-associated retinal de novo lipogenesis ∼70% over control levels. This shift was primarily because of activation of fatty acid synthase (FAS), a rate-limiting enzyme in the biogenic pathway. Activation of FAS was driven by canonical glucose-mediated disinhibition of acetyl-CoA carboxylase, a major upstream regulatory enzyme. Mutant mice expressing gain-of-function FAS demonstrated increased vulnerability to DR, whereas those with FAS deletion in rod photoreceptors maintained preserved visual responses upon induction of diabetes. Excess retinal de novo lipogenesis—either because of diabetes or because of FAS gain of function—was associated with modestly increased levels of palmitate-containing phosphatidylcholine species in synaptic membranes, a finding with as yet uncertain significance. These findings implicate glucose-dependent increases in photoreceptor de novo lipogenesis in the early pathogenesis of DR, although the mechanism of deleterious action of this pathway remains unclear. Therapy for diabetic retinopathy (DR), a common cause of visual disability, has evolved greatly over the past 2 decades but remains ineffective for up to one-third of patients (1Blinder K.J. Dugel P.U. Chen S. Jumper J.M. Walt J.G. Hollander D.A. Scott L.C. Anti-VEGF treatment of diabetic macular edema in clinical practice: Effectiveness and patterns of use (ECHO study report 1).Clin. Ophthalmol. 2017; 11: 393-401Crossref PubMed Scopus (73) Google Scholar). Development of new strategies for treatment could be facilitated by gaining better insight into the pathophysiology of early stage DR. Abnormalities in retinal lipid metabolism occur early in the course of diabetes and are therefore attractive candidat","journal":"Journal of Biological Chemistry","year":2021,"id":184920,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9472,"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":740845,"name":"Beau Sylvester","orcid":"0000-0003-4917-408X","position":1,"is_corresponding":false},{"id":233145,"name":"Sheng Zhang","orcid":"0000-0001-8206-1007","position":2,"is_corresponding":false},{"id":665041,"name":"Sangeeta Adak","orcid":"0000-0003-3855-9099","position":3,"is_corresponding":false},{"id":740846,"name":"Xiaochao Wei","orcid":"0000-0003-4230-7126","position":4,"is_corresponding":false},{"id":740847,"name":"Megan Bowers","orcid":"0000-0002-5930-7635","position":5,"is_corresponding":false},{"id":740848,"name":"Sebastian Jessberger","orcid":"0000-0002-0056-8275","position":6,"is_corresponding":false},{"id":406483,"name":"Fong‐Fu Hsu","orcid":"0000-0001-5368-0183","position":7,"is_corresponding":false},{"id":241850,"name":"Clay F. Semenkovich","orcid":"0000-0003-1163-1871","position":8,"is_corresponding":false},{"id":529057,"name":"Rithwick Rajagopal","orcid":"0000-0002-3036-2665","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T23:48:34.992499Z","pmid":"34425110","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":[]}