The Combined Hyperlipidemia Caused by Impaired Wnt-LRP6 Signaling Is Reversed by Wnt3a Rescue

• Mice with LRP6R611C mutation develop combined hyperlipidemia (CHL)
• LRP6 mutation triggers Sp1-dependent activation of IGF1, AKT, mTORC1, and mTORC2
• These changes enhance lipogenesis, TG and cholesterol synthesis, and VLDL secretion
• Wnt3a treatment reduces plasma lipid levels and liver fat in LRP6R611C mice

SummaryThe 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 LRP6R611C mutation similarly developed elevated plasma LDL and TG levels and fatty liver. Further investigation showed that LRP6R611C 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 LRP6R611C mice with either the IGF1R antagonist PPP, rapamycin, or rmWnt3a. Strikingly, in vivo administration of rmWnt3a to LRP6R611C 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.

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