MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex.
Rett syndrome (RTT; OMIM 312750), a progressive neurological disorder, is caused by mutations in methyl-CpG-binding protein 2 (MECP2; OMIM 300005), a ubiquitously expressed factor. A genetic suppressor screen designed to identify therapeutic targets surprisingly revealed that downregulation of the cholesterol biosynthesis pathway improves neurological phenotypes in Mecp2 mutant mice. Here, we show that MeCP2 plays a direct role in regulating lipid metabolism. Mecp2 deletion in mice results in a host of severe metabolic defects caused by lipid accumulation, including insulin resistance, fatty liver, perturbed energy utilization, and adipose inflammation by macrophage infiltration. We show that MeCP2 regulates lipid homeostasis by anchoring the repressor complex containing NCoR1 and HDAC3 to its lipogenesis targets in hepatocytes. Consistently, we find that liver targeted deletion of Mecp2 causes fatty liver disease and dyslipidemia similar to HDAC3 liver-specific deletion. These findings position MeCP2 as a novel component in metabolic homeostasis. Rett syndrome patients also show signs of peripheral dyslipidemia; thus, together these data suggest that RTT should be classified as a neurological disorder with systemic metabolic components. We previously showed that treatment of Mecp2 mice with statin drugs alleviated motor symptoms and improved health and longevity. Lipid metabolism is a highly treatable target; therefore, our results shed light on new metabolic pathways for treatment of Rett syndrome.
Genetics and Genome Biology Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada.|Department of Molecular and Human Genetics.
Stephanie M
SM
Kyle
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX 77030, USA.
Pradip K
PK
Saha
Department of Molecular and Human Genetics.
Hannah M
HM
Brown
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX 77030, USA.
Lawrence C
LC
Chan
Genetics and Genome Biology Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada monica.justice@sickkids.ca.|Department of Molecular and Human Genetics.|Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada.
Monica J
MJ
Justice
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006655:Histone Deacetylases / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D009154:Mutation; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics; D015518:Rett Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion; D000099186:Histone Deacetylase 3
D006655:Histone Deacetylases; D051783:Methyl-CpG-Binding Protein 2; D056971:Nuclear Receptor Co-Repressor 1; D000099186:Histone Deacetylase 3; C497392:MECP2 protein, human; C497393:Mecp2 protein, mouse; C539128:Ncor1 protein, mouse