ArticleJCI insight2022
SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface.
Article in JCI insight, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 21 citations in OpenAlex.
- tRNA‑derived RNAs in hepatic diseases: From biological functions to clinical translation (Review).International journal of molecular medicine · 2026Review
- Akkermansia: A Potential Target for Natural Botanicals in Treatment of Nonalcoholic Fatty Liver Diseases.Chinese journal of integrative medicine · 2026Review
- Lipid metabolism-MAFLD crosstalk: mechanisms and therapy.Frontiers in endocrinology · 2026Review
- Challenges in the diagnosis and treatment of genetic cholestasis in adults.JHEP reports : innovation in hepatology · 2026Review
- Protein Kinase C Family: Structures, Biological Functions, Diseases, and Pharmaceutical Interventions.MedComm · 2025Review
- Semaphorin 7a is protective through immune modulation during acetaminophen-induced liver injury.Journal of inflammation (London, England) · 2025Article
- STING-mediated IL-6 Inhibits OATP1B1 Expression via the TCF4 Signaling Pathway in Cholestasis.Journal of clinical and translational hepatology · 2024Article
- Phosphorylation: new star of pathogenesis and treatment in steatotic liver disease.Lipids in health and disease · 2024Article
- Multi-omics analysis of a fatty liver model using human hepatocyte chimeric mice.Scientific reports · 2024Article
- Loss ofZoological research · 2024Article
- A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing.Cellular & molecular immunology · 2023Article
- Semaphorin 7A interacts with nuclear factor NF-kappa-B p105 via integrin β1 and mediates inflammation.Cell communication and signaling : CCS · 2023Article
- Do Semaphorins Play a Role in Development of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease?Biomedicines · 2022Article
- CCN1/Integrin αNutrients · 2022Article
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Authors and funding
20 authors at 4 institutions in 3 countries.
Funding
Abstract
Genetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD). Semaphorin7a (Sema7a) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with SEMA7A heterozygous mutations in 470 patients with biopsy-proven NAFLD. SEMA7A heterozygous mutations increased susceptibility to NAFLD, steatosis severity, and NAFLD activity scores in humans and mice. The Sema7aR145W mutation (equivalent to human SEMA7AR148W) significantly induced small lipid droplet accumulation in mouse livers compared with WT mouse livers. Mechanistically, the Sema7aR145W mutation increased N-glycosylated Sema7a and its receptor integrin β1 proteins in the cell membranes of hepatocytes. Furthermore, Sema7aR145W mutation enhanced its protein interaction with integrin β1 and PKC-α and increased PKC-α phosphorylation, which were both abrogated by integrin β1 silencing. Induction of PKCα_WT, but not PKCα_dominant negative, overexpression induced transcriptional factors Srebp1, Chrebp, and Lxr expression and their downstream Acc1, Fasn, and Cd36 expression in primary mouse hepatocytes. Collectively, our findings demonstrate that the SEMA7AR148W mutation is a potentially new strong genetic determinant of NAFLD and promotes intrahepatic lipid accumulation and NAFLD in mice by enhancing PKC-α-stimulated FA and triglyceride synthesis and FA uptake. The inhibition of hepatic PKC-α signaling may lead to novel NAFLD therapies.
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