{"doi":"10.1016/j.jcmgh.2020.10.013","title":"Lymphatic Dysfunction as a Novel Therapeutic Target in Nonalcoholic Steatohepatitis","abstract":"The primary function of the lymphatic system in the liver is to collect interstitial fluid (lymph) and drain it to lymph nodes through lymphatic capillaries, ultimately returning it to the systemic circulation. Lymphatic capillaries consist of one layer of lymphatic endothelial cells (LECs) with unique button-like junctions allowing proteins, lipoproteins, and immune cells in interstitial fluid to be taken in. Alterations in these functionally specialized LEC junctions may impair LEC permeability and drainage functions, contributing to disease pathogenesis. In liver diseases, the number of hepatic lymphatic vessels generally increases. However, questions remain as to how increased lymphatic vessels are related to liver pathology and whether the function of LECs is altered in liver diseases. Despite its apparent importance, the hepatic lymphatic system has not been adequately studied. In a study published in the current issue of Cellular and Molecular Gastroenterology and Hepatology, Burchill et al1Burchill M.A. Finlon J.M. Goldberg A.R. et al.Oxidized low-density lipoprotein drives dysfunction of the liver lymphatic system.Cell Mol Gastroenterol Hepatol. 2021; 11: 573-595Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar demonstrated that alterations of LEC identity and function could lead to the development of nonalcoholic steatohepatitis (NASH). They first evaluated lymphatic vessel numbers in the livers of NASH patients with different pathologic stages and showed a positive correlation between lymphatic vessel numbers and NASH staging. Consistently, an increase in lymphatic vessels was also observed in mice with NASH. Second, with single-cell RNA sequencing (scRNA-seq) analysis of LECs isolated from control and NASH mice, they showed that transcripts important for the identify of LECs, such as Prox-1, Lyve-1, podoplanin, and Vegfr3, were significantly decreased in NASH despite an increase in lymphatic vessels, pointing to a change in the identity and function of LECs. Third, they showed a reduction in the hepatic lymphatic drainage function in NASH mice, which was restored by recombinant vascular endothelial growth factor C (rVEGF-C), the best-known lymphangiogenic factor, with a concomitant reduction in hepatic inflammation. Regarding the mechanism underlying impaired hepatic lymphatic drainage, the same authors previously reported that oxidized low-density lipoprotein (oxLDL), highly elevated in serum of both patients2Ampuero J. Ranchal I. Gallego-Duran R. et al.Oxidized low-density lipoprotein antibodies/high-density lipoprotein cholesterol ratio is linked to advanced non-alcoholic fatty liver disease lean patients.J Gastroenterol Hepatol. 2016; 31: 1611-1618Crossref PubMed Scopus (20) Google Scholar and mice3Zucker S. Hymowitz M. Rollo E.E. et al.Tumorigenic potential of extracellular matrix metalloproteinase inducer.Am J Pathol. 2001; 158: 1921-1928Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar with NASH, was capable of suppressing Prox-1 and its related gene,Vegfr3, in LECs in vitro.4Tamburini B.A.J. Finlon J.M. Gillen A.E. et al.Chronic liver disease in humans causes expansion and differentiation of liver lymphatic endothelial cells.Front Immunol. 2019; 10: 1036Crossref PubMed Scopus (20) Google Scholar On the basis of this observation and the finding from scRNA-seq analysis in the current study, they postulated that oxLDL might alter LEC function through transforming LECs to vascular EC-like cells, leading to decreased permeability and lymphatic drainage in mice with NASH. The authors showed that wild-type mice treated with oxLDL exhibited a significant reduction in lymphatic drainage, recapitulating the situation observed in NASH mice. Furthermore, in an in vitro setting, oxLDL treatment decreased permeability of single-layer LECs, increased expression of vascular endothelial cadherin, a junction protein, and increased the ratio of Vegfr2/Vegfr3 in these cells. These changes are ","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2020,"id":131698,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"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":437273,"name":"Yasuko Iwakiri","orcid":"0000-0001-8032-5654","position":1,"is_corresponding":false},{"id":554989,"name":"Jain Jeong","orcid":null,"position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-18T23:16:03.875886Z","pmid":"33220266","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":[]}