title: The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue.
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.
authors: Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
authors: Gwang-Woong
authors: GW
authors: Go
authors: Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
authors: Roshni
authors: R
authors: Srivastava
authors: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors: Antonio
authors: A
authors: Hernandez-Ono
authors: Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
authors: Gyoungok
authors: G
authors: Gang
authors: Department of Animal Science, Texas A&M University, College Station, TX 77843, USA.
authors: Stephen B
authors: SB
authors: Smith
authors: Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors: Carmen J
authors: CJ
authors: Booth
authors: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors: Henry N
authors: HN
authors: Ginsberg
authors: 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.
authors: Arya
authors: A
authors: Mani
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D002478:Cells, Cultured; D005234:Fatty Liver / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D065626:Non-alcoholic Fatty Liver Disease; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D060509:Wnt3A Protein / Q000378:metabolism
chemical_list: D060488:Low Density Lipoprotein Receptor-Related Protein-6; D046912:Multiprotein Complexes; D060509:Wnt3A Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases