The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance

Wijers, Melinde; Zanoni, Paolo; Liv, Nalan; Vos, Dyonne; Jäckstein, Michelle Y.; Smit, Marieke; Wilbrink, Sanne; Wolters, Justina C.; Veen, Ydwine T. van der; Huijkman, Nicolette; Dekker, Daphne; Kloosterhuis, Niels J.; Dijk, Theo H. van; Billadeau, Daniel D.; Kuipers, Folkert; Klumperman, Judith; Eckardstein, Arnold von; Kuivenhoven, Jan Albert; Sluis, Bart van de

doi:10.1172/jci.insight.126462

Cited by 29 publications

(25 citation statements)

References 74 publications

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“…In addition, several CNVs were observed in our case. The WASH complex acts as a regulator of LDL and HDL metabolism ( 43 ). CACNA1B mutations have been reported to be a distinct myoclonus-dystonia syndrome ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Primary Thyroid NUT Carcinoma With High PD-L1 Expression and Novel Massive IGKV Gene Fusions: A Case Report With Treatment Implications and Literature Review

et al. 2022

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BackgroundNuclear protein in testis (NUT) carcinoma (NC) is a rare and aggressive undifferentiated carcinoma that typically arises from midline supradiaphragmatic structures. It is uniquely driven by a NUT gene rearrangement on chromosome 15q14. Few thyroid NCs have been reported and there are no established treatment guidelines for NUT carcinoma.MethodUltrasound-guided fine needle aspiration smear was performed for the preoperative diagnosis of thyroid lesions. Cytopathology, histology, and immunochemical staining all indicated NC. Fluorescence in situ hybridization (FISH), qRT-PCR, and next-generation sequencing (NGS) were used to analyze the genetic characteristics of NC.ResultsWe describe a rare case of thyrogenic NC in a 38-year-old male with cytological, histological, immunohistochemical, and genetic features. Cytological smears and histopathological specimens showed typical features of NC. Immunohistochemistry confirmed strong immunoreactivity with NUT, EMA, P63, TTF-1, and c-myc. CK19 was positive exclusively in sudden keratosis. No immunoreactivity was found for neuroendocrine markers. FISH was applied to isolate the NUT gene on chromosome 15q14. The NGS results revealed a BRD4-NUT gene fusion, which was further confirmed by RT-qPCR. Structural variation (SV) of NUTM1 occurred in the exon region, and the mutation site was 15q14. Moreover, BRD4 single-nucleotide variation (SNV) occurs in the 3′ UTR at mutation site 19p13.12. The PD-L1 combined predictive score was over 30%. The patient received chemotherapy, followed by programmed cell death 1 (PD-1) inhibition with camrelizumab, and died 10 months after surgery.ConclusionThyroid NC is an extremely rare and fatal malignant tumor. It is necessary to consider NC when squamous differentiation is observed cytologically or histologically. NGS is an effective tool for obtaining the final diagnosis and obtaining a better understanding of tumor pathogenesis. A large number of IGKV gene fusions in addition to the BRD4-NUT fusion may play a role in the pathogenesis and immunotherapy response of NC. Immunotherapy for NC remains to be explored due to the rarity of this aggressive malignancy.

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Section: Discussionmentioning

confidence: 99%

Primary Thyroid NUT Carcinoma With High PD-L1 Expression and Novel Massive IGKV Gene Fusions: A Case Report With Treatment Implications and Literature Review

et al. 2022

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“…Individual plasma samples were fractionated by FPLC, as previously described [ 28 ]. The samples were pooled and the following fractions 36–40, 41–45, 46–50, and 50–55 were used for targeted liquid chromatography-mass spectrometry analysis to determine Apolipoprotein B (ApoB) protein in FPLC fractions, as previously described [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis

Heida

Gruben

Catrysse

et al. 2021

Molecular Metabolism

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Objective Obesity-related chronic inflammation plays an important role in the development of Metabolic Associated Fatty Liver Disease (MAFLD). Although the contribution of the pro-inflammatory NF-κB signaling pathway to the progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is well-established, its role as an initiator of hepatic steatosis and the underlying mechanism remains unclear. Here, we investigated the hypothesis that the hepatocytic NF-κB signaling pathway acts as a metabolic regulator, thereby promoting hepatic steatosis development. Methods A murine model expressing a constitutively active form of IKKβ in hepatocytes (Hep-IKKβca) was used to activate hepatocyte NF-κB. In addition, IKKβca was also expressed in hepatocyte A20-deficient mice (IKKβca;A20 LKO ). A20 is an NF-κB-target gene that inhibits the activation of the NF-κB signaling pathway upstream of IKKβ. These mouse models were fed a sucrose-rich diet for 8 weeks. Hepatic lipid levels were measured and using [1– 13 C]-acetate de novo lipogenesis and cholesterol synthesis rate were determined. Gene expression analyses and immunoblotting were used to study the lipogenesis and cholesterol synthesis pathways. Results Hepatocytic NF-κB activation by expressing IKKβca in hepatocytes resulted in hepatic steatosis without inflammation. Ablation of hepatocyte A20 in Hep-IKKβca mice (IKKβca;A20 LKO mice) exacerbated hepatic steatosis, characterized by macrovesicular accumulation of triglycerides and cholesterol, and increased plasma cholesterol levels. Both De novo lipogenesis (DNL) and cholesterol synthesis were found elevated in IKKβca;A20 LKO mice. Phosphorylation of AMP-activated kinase (AMPK) - a suppressor in lipogenesis and cholesterol synthesis - was decreased in IKKβca;A20 LKO mice. This was paralleled by elevated protein levels of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) and reduced phosphorylation of HMG-CoA reductase (HMGCR) both key enzymes in the cholesterol synthesis pathway. Whereas inflammation was not observed in young IKKβca;A20 LKO mice sustained hepatic NF-κB activation resulted in liver inflammation, together with elevated hepatic and plasma cholesterol levels in middle-aged mice. Conclusions The hepatocytic IKK:NF-κB axis is a metabolic regulator by controlling DNL and cholesterol synthesis, independent of its central role in inflammation. The IKK:NF-κB axis controls the phosphorylation levels of AMPK and HMGCR and the protein levels of HMGCS1. Chronic IKK-mediated NF-κB activation may contribute to the initiation of hepatic steatosis and cardiovascular disease risk in MAFLD patients.

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“…The whole consortium gathered face-toface once each year; the coordinator planned regular site visits (during the first three years) to ensure synergy between the partners. The TransCard results significantly increased our understanding of intracellular lipoprotein receptor trafficking [9][10][11][12]. Using a whole-genome knockdown approach, the consortium also identified a series of new genes that regulate plasma lipid levels through affecting hepatic lipoprotein uptake [13,14].…”

Section: Characterisation and Validationmentioning

confidence: 99%

Sharing lessons learnt across European cardiovascular research consortia

Jong¹,

Bobeldijk-Pastorova²,

Erdmann

et al. 2020

Drug Discovery Today

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The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance

Cited by 29 publications

References 74 publications

Primary Thyroid NUT Carcinoma With High PD-L1 Expression and Novel Massive IGKV Gene Fusions: A Case Report With Treatment Implications and Literature Review

Primary Thyroid NUT Carcinoma With High PD-L1 Expression and Novel Massive IGKV Gene Fusions: A Case Report With Treatment Implications and Literature Review

The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis

Sharing lessons learnt across European cardiovascular research consortia

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