The prorenin receptor and its soluble form contribute to lipid homeostasis

Eva Gatineau, Gertrude Arthur, Audrey Poupeau, Kellea Nichols, Brett T. Spear, Nathan R. Shelman, Gregory A. Graf, Ryan E. Temel, Frederique B. Yiannikouris

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Obesity is associated with alterations in hepatic lipid metabolism. We previously identified the prorenin receptor (PRR) as a potential contributor to liver steatosis. Therefore, we aimed to determine the relative contribution of PRR and its soluble form, sPRR, to lipid homeostasis. PRR-floxed male mice were treated with an adeno-associated virus with thyroxine-binding globulin promoter-driven Cre to delete PRR in the liver [liver PRR knockout (KO) mice]. Hepatic PRR deletion did not change the body weight but increased liver weights. The deletion of PRR in the liver decreased peroxisome proliferator-activated receptor gamma (PPARc) and triglyceride levels, but liver PRR KO mice exhibited higher plasma cholesterol levels and lower hepatic low-density lipoprotein receptor (LDLR) and Sortilin 1 (SORT1) proteins than control (CTL) mice. Surprisingly, hepatic PRR deletion elevated hepatic cholesterol, and up-regulated hepatic sterol regulatory element-binding protein 2 (SREBP2) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-R) genes. In addition, the plasma levels of sPRR were significantly higher in liver PRR KO mice than in controls. In vitro studies in HepG2 cells demonstrated that sPRR treatment upregulated SREBP2, suggesting that sPRR could contribute to hepatic cholesterol biosynthesis. Interestingly, PRR, total cleaved and noncleaved sPRR contents, furin, and Site-1 protease (S1P) were elevated in the adipose tissue of liver PRR KO mice, suggesting that adipose tissue could contribute to the circulating pool of sPRR. Overall, this work supports previous works and opens a new area of investigation concerning the function of sPRR in lipid metabolism and adipose tissue-liver cross talk. NEW & NOTEWORTHY Hepatic PRR and its soluble form, sPRR, contribute to triglyceride and cholesterol homeostasis and hepatic inflammation. Deletion of hepatic PRR decreased triglyceride levels through a PRR-PPARc-dependent mechanism but increased hepatic cholesterol synthesis through sPRR-medicated upregulation of SREBP-2. Our study highlighted a new paradigm of cross talk between the liver and the adipose tissue involving cholesterol and sPRR.

Original languageEnglish
Pages (from-to)E609-E618
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume320
Issue number3
DOIs
StatePublished - Mar 2021

Bibliographical note

Publisher Copyright:
© 2021 the American Physiological Society

Funding

We thank Sierra Schlicht and Ailing Ji for contribution to the FPLC analysis and Dr. Lei Cai from Dr. Ryan Temel's laboratory for help with liver lipids extraction. This work was supported by NIH Grant R01-HL-142969, the American Heart Association Grant 13SDG17230008, the National Institute of General Medical Sciences Grant P30 GM127211, and the University of Kentucky, Center for Clinical and Translational Sciences Grant UL1TR001998. This work was supported by NIH Grant R01-HL-142969, the American Heart Association Grant 13SDG17230008, the National Institute of General Medical Sciences Grant P30 GM127211, and the University of Kentucky, Center for Clinical and Translational Sciences Grant UL1TR001998.

FundersFunder number
FPLC
National Institutes of Health (NIH)R01-HL-142969
National Institute of General Medical SciencesP30 GM127211
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK113625
American Heart Association13SDG17230008
University of Kentucky, Center for Clinical and Translational ScienceUL1TR001998

    Keywords

    • Adipose tissue
    • Lipid homeostasis
    • Liver
    • PRR
    • SPRR

    ASJC Scopus subject areas

    • General Medicine

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