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 de Boer; Folkert Kuipers; Antoine Rimbert; Giuseppe D Norata; Anke Loregger; Noam Zelcer

doi:10.1038/s41467-023-40943-1

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 de Boer, Folkert Kuipers, Antoine Rimbert, Giuseppe D Norata, Anke Loregger, Noam Zelcer^*

^*Corresponding author for this work

Center for Liver, Digestive and Metabolic Diseases (CLDM)

Research output: Contribution to journal › Article › Academic › peer-review

7 Citations (Scopus)

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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.

Original language	English
Article number	5181
Number of pages	15
Journal	Nature Communications
Volume	14
DOIs	https://doi.org/10.1038/s41467-023-40943-1
Publication status	Published - 25-Aug-2023

Keywords

Humans
Female
Male
Animals
Mice
Sterol Regulatory Element Binding Protein 1/genetics
Lipid Metabolism/genetics
Liver
Hepatocytes
Lipoproteins, HDL

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SPRING-dependent regulation of hepatic SREBP signaling governs systemic lipid metabolism in mice and humans - raw proteomics files
Hendrix, S. (Creator), Valiloo, M. (Creator), Kingma, J. (Creator), Ottenhof, R. (Creator), Zijlstra, L. (Creator), Sachdev, V. (Creator), Svecla, M. (Creator), Jongejan, A. (Creator), Kuipers, F. (Creator), Brummelkamp, T. (Creator), Rimbert, A. (Creator), Loregger, A. (Creator) & Zelcer, N. (Creator), figshare, 28-Jun-2023
DOI: 10.6084/m9.figshare.22699408.v1, https://figshare.com/articles/dataset/SPRING-dependent_regulation_of_hepatic_SREBP_signaling_governs_systemic_lipid_metabolism_in_mice_and_humans_-_raw_proteomics_files/22699408/1
Dataset
Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans
Hendrix, S. (Creator), Valiloo, M. (Creator), Kingma, J. (Creator), Ottenhof, R. (Creator), Zijlstra, L. (Creator), Sachdev, V. (Creator), Svecla, M. (Creator), Jongejan, A. (Creator), Kuipers, F. (Creator), Brummelkamp, T. (Creator), Rimbert, A. (Creator), Norata, G. D. (Creator), Loregger, A. (Creator) & Zelcer, N. (Creator), figshare, 28-Jul-2023
DOI: 10.6084/m9.figshare.22699408, https://figshare.com/articles/dataset/SPRING-dependent_regulation_of_hepatic_SREBP_signaling_governs_systemic_lipid_metabolism_in_mice_and_humans_-_raw_proteomics_files/22699408
Dataset

Cite this

Hendrix, S., Kingma, J., Ottenhoff, R., Valiloo, M., Svecla, M., Zijlstra, L. F., Sachdev, V., Kovac, K., Levels, J. H. M., Jongejan, A., de Boer, J. F., Kuipers, F., Rimbert, A., Norata, G. D., Loregger, A., & Zelcer, N. (2023). Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans. Nature Communications, 14, Article 5181. https://doi.org/10.1038/s41467-023-40943-1

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title = "Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans",

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.",

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Hendrix, S, Kingma, J, Ottenhoff, R, Valiloo, M, Svecla, M, Zijlstra, LF, Sachdev, V, Kovac, K, Levels, JHM, Jongejan, A, de Boer, JF , Kuipers, F, Rimbert, A, Norata, GD, Loregger, A & Zelcer, N 2023, 'Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans', Nature Communications, vol. 14, 5181. https://doi.org/10.1038/s41467-023-40943-1

TY - JOUR

T1 - Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans

AU - Hendrix, Sebastian

AU - Kingma, Jenina

AU - Ottenhoff, Roelof

AU - Valiloo, Masoud

AU - Svecla, Monika

AU - Zijlstra, Lobke F

AU - Sachdev, Vinay

AU - Kovac, Kristina

AU - Levels, Johannes H M

AU - Jongejan, Aldo

AU - de Boer, Jan F

AU - Kuipers, Folkert

AU - Rimbert, Antoine

AU - Norata, Giuseppe D

AU - Loregger, Anke

AU - Zelcer, Noam

PY - 2023/8/25

Y1 - 2023/8/25

N2 - 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.

AB - 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.

KW - Humans

KW - Female

KW - Male

KW - Animals

KW - Mice

KW - Sterol Regulatory Element Binding Protein 1/genetics

KW - Lipid Metabolism/genetics

KW - Liver

KW - Hepatocytes

KW - Lipoproteins, HDL

U2 - 10.1038/s41467-023-40943-1

DO - 10.1038/s41467-023-40943-1

M3 - Article

C2 - 37626055

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

M1 - 5181

ER -

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

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Keywords

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SPRING-dependent regulation of hepatic SREBP signaling governs systemic lipid metabolism in mice and humans - raw proteomics files

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

Cite this