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Heida A, Gruben N, Catrysse L, et al. The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis. Mol Metab. 2021;54:101349doi: 10.1016/j.molmet.2021.101349.
Heida, A., Gruben, N., Catrysse, L., Koehorst, M., Koster, M., Kloosterhuis, N. J., Gerding, A., Havinga, R., Bloks, V. W., Bongiovanni, L., Wolters, J. C., van Dijk, T., van Loo, G., de Bruin, A., Kuipers, F., Koonen, D. P. Y., & van de Sluis, B. (2021). The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis. Molecular metabolism, 54101349. https://doi.org/10.1016/j.molmet.2021.101349
Heida, Andries, et al. "The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis." Molecular metabolism vol. 54 (2021): 101349. doi: https://doi.org/10.1016/j.molmet.2021.101349
Heida A, Gruben N, Catrysse L, Koehorst M, Koster M, Kloosterhuis NJ, Gerding A, Havinga R, Bloks VW, Bongiovanni L, Wolters JC, van Dijk T, van Loo G, de Bruin A, Kuipers F, Koonen DPY, van de Sluis B. The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis. Mol Metab. 2021 Oct 06;54:101349. doi: 10.1016/j.molmet.2021.101349. Epub 2021 Oct 06. PMID: 34626855; PMCID: PMC8581577.
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Mol Metab. 2021 Oct 06;54:101349. doi: 10.1016/j.molmet.2021.101349. Epub 2021 Oct 06.

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

Molecular metabolism

Andries Heida, Nanda Gruben, Leen Catrysse, Martijn Koehorst, Mirjam Koster, Niels J Kloosterhuis, Albert Gerding, Rick Havinga, Vincent W Bloks, Laura Bongiovanni, Justina C Wolters, Theo van Dijk, Geert van Loo, Alain de Bruin, Folkert Kuipers, Debby P Y Koonen, Bart van de Sluis

Affiliations

  1. Departments of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  2. VIB Inflammation Research Center, Ghent University, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  3. Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, the Netherlands; Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy.
  4. Departments of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  5. Departments of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, the Netherlands.
  6. Departments of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Departments of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  7. Departments of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: [email protected].
  8. Departments of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: [email protected].

PMID: 34626855 PMCID: PMC8581577 DOI: 10.1016/j.molmet.2021.101349

Abstract

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

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

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.

Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Keywords: Cardiovascular disease; Hypercholesterolemia; Inflammation; Lipid metabolism; Mevalonate pathway; Steatosis

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