Knock-out of IKKepsilon ameliorates atherosclerosis and fatty liver disease by alterations of lipid metabolism in the PCSK9 model in mice
The inhibitor-kappaB kinase epsilon (IKKε) represents a non-canonical IκB kinase that modulates NF-κB activity and interferon I responses. Inhibition of this pathway has been linked with atherosclerosis and metabolic dysfunction-associated steatotic liver disease (MASLD), yet the results are contrad...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
5 October 2024
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| In: |
International journal of molecular sciences
Year: 2024, Volume: 25, Issue: 19, Pages: 1-12 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms251910721 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.3390/ijms251910721 Verlag, kostenfrei, Volltext: https://www.mdpi.com/1422-0067/25/19/10721 
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| Author Notes: | Ulrike Weiss, Eleonora Mungo, Michelle Haß, Denis Benning, Robert Gurke, Lisa Hahnefeld, Erika Dorochow, Jessica Schlaudraff, Tobias Schmid, Silvia Kuntschar, Sofie Meyer, Rebekka Medert, Marc Freichel, Gerd Geisslinger and Ellen Niederberger |
| Summary: | The inhibitor-kappaB kinase epsilon (IKKε) represents a non-canonical IκB kinase that modulates NF-κB activity and interferon I responses. Inhibition of this pathway has been linked with atherosclerosis and metabolic dysfunction-associated steatotic liver disease (MASLD), yet the results are contradictory. In this study, we employed a combined model of hepatic PCSK9D377Y overexpression and a high-fat diet for 16 weeks to induce atherosclerosis and liver steatosis. The development of atherosclerotic plaques, serum lipid concentrations, and lipid metabolism in the liver and adipose tissue were compared between wild-type and IKKε knock-out mice. The formation and progression of plaques were markedly reduced in IKKε knockout mice, accompanied by reduced serum cholesterol levels, fat deposition, and macrophage infiltration within the plaque. Additionally, the development of a fatty liver was diminished in these mice, which may be attributed to decreased levels of multiple lipid species, particularly monounsaturated fatty acids, triglycerides, and ceramides in the serum. The modulation of several proteins within the liver and adipose tissue suggests that de novo lipogenesis and the inflammatory response are suppressed as a consequence of IKKε inhibition. In conclusion, our data suggest that the knockout of IKKε is involved in mechanisms of both atherosclerosis and MASLD. Inhibition of this pathway may therefore represent a novel approach to the treatment of cardiovascular and metabolic diseases. |
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| Item Description: | Gesehen am 01.04.2025 |
| Physical Description: | Online Resource |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms251910721 |