Carbamazepine Enhances Adipogenesis by Inhibiting Wnt/β-Catenin Expression

Im, Dong Uk; Kim, Sang Chon; Chau, Gia Cac; Um, Sung Hee

doi:10.3390/cells8111460

Cited by 23 publications

(22 citation statements)

References 51 publications

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“…44 The antiepileptic drug carbamazepine (an inhibitor of voltage-gated sodium channels 45 ) has been shown to decrease Wnt/β-catenin signaling in the human colon adenocarcinoma SW480 cell line 34 and mouse adipocyte 3T3-L1 cells. 33 The results presented here contribute further evidence that Wnt signaling modulation may be involved in carbamazepine treatment of epilepsy. This warrants further studies of the role of Wnt-FZD8 signaling modulation in the therapeutic mechanism of carbamazepine against epilepsy.…”

Section: ■ Discussion and Conclusionsupporting

confidence: 64%

Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8

et al. 2020

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Misregulation of Wnt signaling is common in human cancer. The development of small molecule inhibitors against the Wnt receptor, frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated that carbamazepine can suppress FZD8-mediated Wnt/β-catenin signaling. We determined the crystal structure of the complex at 1.7 Å resolution, which reveals that carbamazepine binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely related FZD5 and other FZDs for carbamazepine binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed carbamazepine-mediated Wnt signaling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term carbamazepine treatment.

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Section: ■ Discussion and Conclusionsupporting

confidence: 64%

Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8

et al. 2020

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“…A recent study showed that raloxifene could reduce fat accumulation and suppress the activation of adipogenic factors by preserving the expression of canonical Wnt10b/β-catenin 45 . Moreover, carbamazepine inhibits Wnt/β-catenin expression and enhances adipogenesis 46 . In addition to the function of β-catenin in adipogenesis, a disruption of OCT4 and β-catenin recruitment to target gene promoters may affect differentiation, pluripotency, and cell cycle genes 47 .…”

Section: Discussionmentioning

confidence: 99%

Oxysterol-binding protein-like 2 contributes to the developmental progression of preadipocytes by binding to β-catenin

et al. 2021

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Oxysterol-binding protein-like 2 (OSBPL2), also known as oxysterol-binding protein-related protein (ORP) 2, is a member of lipid transfer protein well-known for its role in regulating cholesterol homeostasis. A recent study reported that OSBPL2/ORP2 localizes to lipid droplets (LDs) and is associated with energy metabolism and obesity. However, the function of OSBPL2/ORP2 in adipocyte differentiation is poorly understood. Here, we report that OSBPL2/ORP2 contributes to the developmental progression of preadipocytes. We found that OSBPL2/ORP2 binds to β-catenin, a key effector in the Wnt signaling pathway that inhibits adipogenesis. This complex plays a role in regulating the protein level of β-catenin only in preadipocytes, not in mature adipocytes. Our data further indicated that OSBPL2/ORP2 mediates the transport of β-catenin into the nucleus and thus regulates target genes related to adipocyte differentiation. Deletion of OSBPL2/ORP2 markedly reduces β-catenin both in the cytoplasm and in the nucleus, promotes preadipocytes maturation, and ultimately leads to obesity-related characteristics. Altogether, we provide novel insight into the function of OSBPL2/ORP2 in the developmental progression of preadipocytes and suggest OSBPL2/ORP2 may be a potential therapeutic target for the treatment of obesity-related diseases.

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“…De novo mutation of FASN in synaptic transmission genes was detected in epileptic encephalopathies via synaptic dysregulation ( 37 ). Carbamazepine increased the expression levels of FASN, suppressed Wnt/β-catenin expression, and was widely used in the treatment of epilepsy ( 38 ). 17-beta-hydroxysteroid dehydrogenase (HSD17B) plays a crucial role in catalyzing the androgen and estrogen biosynthesis in epileptic human hippocampus ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Acetylation Profiles in the Metabolic Process of Glioma-Associated Seizures

Lin

Zheng

et al. 2021

Front. Neurol.

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Objective: We test the hypothesis that lysine acetylation is involved in the metabolic process of glioma-associated seizures (GAS).Methods: We used label-free mass spectrometry-based quantitative proteomics to quantify dynamic changes of protein acetylation between gliomas with seizure (CA1 group) and gliomas without seizure (CA2 group). Furthermore, differences of acetyltransferase and deacetylase expression between CA1 and CA2 groups were performed by a quantitative proteomic study. We further classified acetylated proteins into groups according to cell component, molecular function, and biological process. In addition, metabolic pathways and protein interaction networks were analyzed. Regulated acetyltransferases and acetylated profiles were validated by PRM and Western blot.Results: We detected 169 downregulated lysine acetylation sites of 134 proteins and 39 upregulated lysine acetylation sites of 35 proteins in glioma with seizures based on acetylome. We detected 407 regulated proteins by proteomics, from which ACAT2 and ACAA2 were the differentially regulated enzymes in the acetylation of GAS. According to the KEGG analysis, the upregulated acetylated proteins within the PPIs were mapped to pathways involved in the TCA cycle, oxidative phosphorylation, biosynthesis of amino acids, and carbon metabolism. The downregulated acetylated proteins within the PPIs were mapped to pathways involved in fatty acid metabolism, oxidative phosphorylation, TCA cycle, and necroptosis. Regulated ACAT2 expression and acetylated profiles were validated by PRM and Western blot.Conclusions: The data support the hypothesis that regulated protein acetylation is involved in the metabolic process of GAS, which may be induced by acetyl-CoA acetyltransferases.

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Carbamazepine Enhances Adipogenesis by Inhibiting Wnt/β-Catenin Expression

Cited by 23 publications

References 51 publications

Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8

Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8

Oxysterol-binding protein-like 2 contributes to the developmental progression of preadipocytes by binding to β-catenin

Acetylation Profiles in the Metabolic Process of Glioma-Associated Seizures

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