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Cell Metab. 2014 Feb 4;19(2):209-20. doi: 10.1016/j.cmet.2013.11.023.

The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue.

Author information

1
Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
2
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
3
Department of Animal Science, Texas A&M University, College Station, TX 77843, USA.
4
Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.
5
Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA. Electronic address: arya.mani@yale.edu.

Abstract

The underlying molecular genetic basis of combined hyperlipidemia, the most common atherogenic lipid disorder, is poorly characterized. Rare, nonconservative mutations in the Wnt coreceptor, LRP6, underlie autosomal dominant atherosclerosis, combined hyperlipidemia, and fatty liver disease. Mice with LRP6(R611C) mutation similarly developed elevated plasma LDL and TG levels and fatty liver. Further investigation showed that LRP6(R611C) mutation triggers hepatic de novo lipogenesis, lipid and cholesterol biosynthesis, and apoB secretion by an Sp1-dependent activation of IGF1, AKT, and both mTORC1 and mTORC2. These pathways were normalized after in vitro treatment of primary hepatocytes from LRP6(R611C) mice with either the IGF1R antagonist PPP, rapamycin, or rmWnt3a. Strikingly, in vivo administration of rmWnt3a to LRP6(R611C) mice normalized the altered expression of enzymes of DNL and cholesterol biosynthesis, and restored plasma TG and LDL levels to normal. These findings identify Wnt signaling as a regulator of plasma lipids and a target for treatment of hyperlipidemia.

PMID:
24506864
PMCID:
PMC3920193
DOI:
10.1016/j.cmet.2013.11.023
[Indexed for MEDLINE]
Free PMC Article

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