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 tr...
Source: Human Molecular Genetics - Category: Genetics & Stem Cells Authors: Tags: ARTICLES Source Type: research

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Source: Journal of Obesity - Category: Eating Disorders & Weight Management Tags: J Obes Source Type: research
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Source: PPAR Research - Category: Genetics & Stem Cells Tags: PPAR Res Source Type: research
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Source: International Journal of Sports Physiology and Performance - Category: Sports Medicine Tags: Int J Sports Physiol Perform Source Type: research
Publication date: Available online 23 September 2020Source: Best Practice &Research Clinical GastroenterologyAuthor(s): Stephen Ip, Rahima A. Bhanji, Maryam Ebadi, Andrew L. Mason, Aldo J. Montano-Loza
Source: Best Practice and Research Clinical Gastroenterology - Category: Gastroenterology Source Type: research
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Source: Experimental and Therapeutic Medicine - Category: General Medicine Tags: Exp Ther Med Source Type: research
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