Chromatin regulator SMARCAL1 modulates cellular lipid metabolism

Author:

Nagai Taylor Hanta,Hartigan Chrissy,Mizoguchi Taiji,Yu HaojieORCID,Deik AmyORCID,Bullock Kevin,Wang Yanyan,Cromley Debra,Schenone MonicaORCID,Cowan Chad A.,Rader Daniel J.,Clish Clary B.ORCID,Carr Steven A.,Xu Yu-XinORCID

Abstract

AbstractBiallelic mutations of the chromatin regulator SMARCAL1 cause Schimke Immunoosseous Dysplasia (SIOD), characterized by severe growth defects and premature mortality. Atherosclerosis and hyperlipidemia are common among SIOD patients, yet their onset and progression are poorly understood. Using an integrative approach involving proteomics, mouse models, and population genetics, we investigated SMARCAL1’s role. We found that SmarcAL1 interacts with angiopoietin-like 3 (Angptl3), a key regulator of lipoprotein metabolism. In vitro and in vivo analyses demonstrate SmarcAL1’s vital role in maintaining cellular lipid homeostasis. The observed translocation of SmarcAL1 to cytoplasmic peroxisomes suggests a potential regulatory role in lipid metabolism through gene expression. SmarcAL1 gene inactivation reduces the expression of key genes in cellular lipid catabolism. Population genetics investigations highlight significant associations between SMARCAL1 genetic variations and body mass index, along with lipid-related traits. This study underscores SMARCAL1’s pivotal role in cellular lipid metabolism, likely contributing to the observed lipid phenotypes in SIOD patients.

Funder

U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute

American Heart Association

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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