ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2015
Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 66 citations in OpenAlex.
- Cell differentiation-related signaling pathways: biological functions, diseases and therapeutic targets.Signal transduction and targeted therapy · 2026Review
- RYK is a GPNMB receptor that drives MASH.Nature · 2026Article
- Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Wnt/β-Catenin Signaling in Liver Pathobiology.Annual review of pathology · 2025Review
- Chinese herbal medicines: the modifier of hepatocellular carcinoma targeting Wnt/β-catenin signaling pathway.Frontiers in pharmacology · 2025Review
- Targeting Wnt Pathways with Small Molecules as New Approach in Cardiovascular Disease.Current cardiology reviews · 2025Review
- Article
- A combined extract containingFood science and biotechnology · 2024Article
- Microarray-based Detection of Critical Overexpressed Genes in the Progression of Hepatic Fibrosis in Non-alcoholic Fatty Liver Disease: A Protein-protein Interaction Network Analysis.Current medicinal chemistry · 2024Article
- Rottlerin suppresses lipid accumulation by inhibiting de novo lipogenesis and adipogenesis via LRP6/mTOR/SREBP1C in 3T3-L1 adipocytes.Food science and biotechnology · 2023Article
- Review
- The identification of metabolites from gut microbiota in NAFLD via network pharmacology.Scientific reports · 2023Article
- Hepatic DKK1-driven steatosis is CD36 dependent.Life science alliance · 2023Article
- Wnt signaling in liver regeneration, disease, and cancer.Clinical and molecular hepatology · 2023Review
- Non-canonical WNT signalling in cardiovascular disease: mechanisms and therapeutic implications.Nature reviews. Cardiology · 2022Review
- Perturbation of Wnt/β-catenin signaling and sexual dimorphism in non-alcoholic fatty liver disease.Hepatology research : the official journal of the Japan Society of Hepatology · 2022Article
- TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut-liver crosstalk.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice.The Journal of clinical investigation · 2022Article
- RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state.Nature communications · 2022Article
- Misregulation of Wnt Signaling Pathways at the Plasma Membrane in Brain and Metabolic Diseases.Membranes · 2021Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, which begins with isolated steatosis and advances to nonalcoholic steatohepatitis (NASH), steatofibrosis, and cirrhosis. The pathways involved in disease progression are not understood. Loss-of-function mutations in Wnt coreceptor LDL receptor-related protein 6 (LRP6) underlie early-onset atherosclerosis, metabolic risk factors, and NAFLD in humans by unknown mechanisms. We generated mice with the human disease-associated LRP6(R611C) mutation and phenotypically characterized their liver. Homozygote LRP6(R611C) (LRP6(mut/mut)) mice exhibited both steatohepatitis and steatofibrosis. These traits were associated with increased activity of the noncanonical Wnt/Ras homolog family member A, Rho-associated protein kinase 2, and PKC-α/-μ pathways. Accordingly, there was increased TGF-β1 activity, coupled with enhanced expression of smooth muscle α-actin and vimentin that colocalized with albumin in LRP6(mut/mut) mouse liver. LRP6 knockdown reprogramed HepG2 cells to express both these markers, linking impaired Wnt signaling with hepatocyte transdifferentiation. The causal link between altered Wnt signaling and NASH was established by normalization of the disease pathways and rescue of the liver traits by Wnt3a administration to LRP6(mut/mut) mice. Thus, this study identifies diverse disease pathways that underlie a spectrum of NASH-related liver diseases and are linked by a single human genetic variant. LRP6 and noncanonical Wnt pathways are important potential therapeutic targets against NASH.
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Registered trials
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