Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans

Sebastian Hendrix, Jenina Kingma, Roelof Ottenhoff, Masoud Valiloo, Monika Svecla, Lobke F. Zijlstra, Vinay Sachdev, Kristina Kovac, Johannes H. M. Levels, Aldo Jongejan, Jan F. Boer, Folkert Kuipers, Antoine Rimbert, Giuseppe D. Norata, Anke Loregger and Noam Zelcer ()
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Sebastian Hendrix: University of Amsterdam
Jenina Kingma: University of Amsterdam
Roelof Ottenhoff: University of Amsterdam
Masoud Valiloo: University of Amsterdam
Monika Svecla: Università degli Studi di Milano
Lobke F. Zijlstra: University of Amsterdam
Vinay Sachdev: University of Amsterdam
Kristina Kovac: University of Amsterdam
Johannes H. M. Levels: University of Amsterdam
Aldo Jongejan: University of Amsterdam
Jan F. Boer: University of Groningen
Folkert Kuipers: University of Groningen
Antoine Rimbert: CNRS, INSERM
Giuseppe D. Norata: Università degli Studi di Milano
Anke Loregger: University of Amsterdam
Noam Zelcer: University of Amsterdam

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. We recently identified SPRING as a post-transcriptional regulator of SREBP activation. Constitutive or inducible global ablation of Spring in mice is not tolerated, and we therefore develop liver-specific Spring knockout mice (LKO). Transcriptomics and proteomics analysis reveal attenuated SREBP signaling in livers and hepatocytes of LKO mice. Total plasma cholesterol is reduced in male and female LKO mice in both the low-density lipoprotein and high-density lipoprotein fractions, while triglycerides are unaffected. Loss of Spring decreases hepatic cholesterol and triglyceride content due to diminished biosynthesis, which coincides with reduced very-low-density lipoprotein secretion. Accordingly, LKO mice are protected from fructose diet-induced hepatosteatosis. In humans, we find common genetic SPRING variants that associate with circulating high-density lipoprotein cholesterol and ApoA1 levels. This study positions SPRING as a core component of hepatic SREBP signaling and systemic lipid metabolism in mice and humans.

Date: 2023
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DOI: 10.1038/s41467-023-40943-1

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