ArticleGastroenterology2016
Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol.
Article in Gastroenterology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 189 papers, 1 of them a synthesis that pooled it.
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Who cites it
189 citing papers in PubMed, 1 synthesis or guideline pooled it, 318 citations in OpenAlex.
- The Mechanism Underlying the Influence of Indole-3-Propionic Acid: A Relevance to Metabolic Disorders.Frontiers in endocrinology · 2022Pooled it
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- PDE3B as a multi-organ therapeutic node in the gut-liver axis of metabolic dysfunction-associated steatohepatitis.Experimental & molecular medicine · 2026Article
- Protective Effects ofJournal of microbiology and biotechnology · 2026Article
- Pre-diagnostic immunological markers of bacterial translocation and liver cancer risk: A nested case-control analysis of 12 prospective cohorts.International journal of cancer · 2026Article
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- Daixie recipe ameliorates diet-induced MASH in miceFrontiers in endocrinology · 2026Article
- Gut microbiota and the gut-liver axis in MASLD: mechanisms, immune regulation and therapeutic opportunities.Frontiers in pharmacology · 2026Review
- Food-derived molecules as regulators of intestinal tight junctions and barrier function: mechanisms and implications.Frontiers in drug delivery · 2026Review
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- The gut-liver-immune axis: structural basis, cellular architecture, molecular mediators, and disease-specific manifestations.Frontiers in immunology · 2026Review
- Associations of clinical indexes and prognosis with gut-vascular barrier damage in patients with intestinal obstruction.World journal of gastrointestinal surgery · 2025Article
- Lack of intestinal Mucin-1 impairs intestinal epithelial barrier and promotes metabolic dysfunction-associated steatotic liver disease in male mice.Nature communications · 2025Article
- Ubiquitination of TFEB increased intestinal permeability to aggravate metabolic dysfunction-associated steatohepatitis.Hepatology (Baltimore, Md.) · 2025Article
- Advances in the acting mechanism and treatment of gut microbiota in metabolic dysfunction-associated steatotic liver disease.Gut microbes · 2025Review
- Gut microbiome in metabolic dysfunction-associated steatotic liver disease and associated hepatocellular carcinoma.Nature reviews. Gastroenterology & hepatology · 2025Review
- Association between Dietary Index for Gut Microbiota (DI-GM) and non-alcoholic fatty liver disease (NAFLD): Evidence from NHANES 1999-2018.Asia Pacific journal of clinical nutrition · 2025Observational
- Intestinal bacteria-derived extracellular vesicles in metabolic dysfunction-associated steatotic liver disease: From mechanisms to therapeutics.Molecules and cells · 2025Review
- Precision targeting of β-catenin induces tumor reprogramming and immunity in hepatocellular cancers.Nature communications · 2025Article
- Resident CD24Acta biochimica et biophysica Sinica · 2025Article
129 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 6 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsThere is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH.
methodsMale C57BL/6 (control) or F11r(-/-) mice were fed a normal diet or a diet high in saturated fat, fructose, and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse-transcription polymerase chain reaction, and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S ribosomal RNA sequencing. We also analyzed biopsy specimens from proximal colons of 30 patients with nonalcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy.
resultsF11r(-/-) mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r(-/-) mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption, and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r(-/-) mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r(-/-) mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r(-/-) mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation.
conclusionsMice with defects in intestinal epithelial permeability develop more severe steatohepatitis after a HFCD than control mice, and colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to the development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH.
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