ArticleJournal of hepatology2022
TTC39B destabilizes retinoblastoma protein promoting hepatic lipogenesis in a sex-specific fashion.
Article in Journal of hepatology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 10 citations in OpenAlex.
- Gene therapy for liver diseases: methods, challenges and opportunities.Journal of nanobiotechnology · 2026Review
- LncRNAs, RNA Therapeutics, and Emerging Technologies in Liver Pathobiology.Seminars in liver disease · 2025Review
- Targeting CDK4/6 in breast cancer.Experimental & molecular medicine · 2025Review
- Molecular Regulation and Therapeutic Targeting of VLDL Production in Cardiometabolic Disease.Cellular and molecular gastroenterology and hepatology · 2025Review
- Restoring metabolic flexibility: targeting organelle interaction networks in the pathogenesis and therapy of MASLD.Frontiers in cell and developmental biology · 2025Review
- Non-canonical pathway for Rb inactivation and external signaling coordinate cell-cycle entry without CDK4/6 activity.Nature communications · 2023Article
- Sequential activation of E2F via Rb degradation and c-Myc drives resistance to CDK4/6 inhibitors in breast cancer.Cell reports · 2023Article
- VAP Proteins - From Organelle Tethers to Pathogenic Host Interactors and Their Role in Neuronal Disease.Frontiers in cell and developmental biology · 2022Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsMolecular mechanisms underlying the different susceptibility of men and women to non-alcoholic fatty liver disease (NAFLD) are poorly understood. The TTC39B locus encodes a scaffolding protein, associates with gynecological disorders and its deletion protects mice from diet-induced steatohepatitis. This study aimed to elucidate the molecular mechanisms linking TTC39B (T39) to the expression of lipogenic genes and to explore sex-specific effects.
methodsCo-expression in HEK293A cells validated the novel T39/pRb interaction predicted by a protein-protein interaction algorithm. T39 was knocked down using an antisense oligonucleotide (ASO) in mice with dietary NAFLD and a genetic deficiency of pRb or its downstream effector E2F1, as well as in primary human hepatocytes.
resultsT39 interacts with pRb via its C-terminal TPR domain and promotes its proteasomal degradation. In female mice, T39 deficiency reduces the mRNA of lipogenic genes, especially Pnpla3, in a pRb- and E2F1-dependent manner. In contrast, in male mice, T39 deficiency results in a much smaller reduction in lipogenic gene expression that is independent of pRb/E2F1. T39 also interacts with VAPB via an N-terminal FFAT motif and stabilizes the interaction of VAPB with SCAP. Ovariectomy abolishes the effect of T39 knockdown on the hepatic pRb/E2F1/Pnpla3 axis. In both sexes T39 knockdown reduces SCAP independently of pRb. In primary human hepatocytes, T39 knockdown reduces expression of PNPLA3 and other lipogenic genes in women but not men.
conclusionsWe have uncovered a conserved sexual dimorphism in the regulation of hepatic lipogenic genes, with effects of T39 mediated through pRb/E2F1 in females and VAPB/SCAP in both sexes. T39 inhibition could be a novel strategy to downregulate PNPLA3 and treat NAFLD in women. LAY SUMMARY: In females, the protein TTC39B degrades a tumor suppressor in the liver to promote the synthesis of new fat and the expression of a major genetic risk factor for non-alcoholic fatty liver disease. TTC39B is a potential therapeutic target for non-alcoholic fatty liver disease, especially in women.
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