SMARCAL1 modulates cellular triglyceride storage and expenditure in response to cell growth states via interaction with ANGPTL3 (RNA-Seq 2)

SMARCAL1 is a chromatin regulator. Biallelic mutations of SMARCAL1 cause Schimke Immunoosseous Dysplasia (SIOD), a disease with severe growth defects and premature death. Atherosclerosis and hyperlipidemia are common phenotypes among SIOD patients. However, little is known about their genesis and development. Here we show that SMARCAL1 is vital in regulating cellular lipid metabolism. Using a proteomic approach, we found that SmarcAL1 interacts with angiopoietin-like 3 (Angptl3), a key lipoprotein regulator. SmarcAL1 deficiency in cell models resulted in substantial accumulation of triglycerides (TGs) and fatty acids (FAs). SmarcAL1 KO in mice drastically increased plasma TG level. The nuclear SmarcAL1 translocates into cytoplasm, surprisingly, enriched at peroxisomes, where it interacts with Angptl3. This shuttling provides a regulatory control over cellular lipid metabolism via SmarcAL1-regulated gene expression, in response to cell growth states. Inactivation of SmarcAL1 gene reduced the expression of the genes responsible for FA metabolism, suggesting that SmarcAL1 plays a key role in regulating lipid metabolism. Indeed, the Angptl3-mediated TG partition is largely dependent on SmarcAL1 activity. This activity was further supported by two opposite SMARCAL1 single-tissue expression profiles linked to two quantitative trait loci that are differentially associated with body mass index. Thus, SMARCAL1 is crucial for cellular lipid metabolism, and ANGPTL3-regulated SMARCAL1 activities enable cells to response to cell growth states for TG storage or expenditure.SMARCAL1是一种染色质调控因子。SMARCAL1的双等位基因突变可引发施基克免疫骨发育不良（Schimke Immunoosseous Dysplasia，SIOD），患者会出现严重生长缺陷并过早死亡。动脉粥样硬化与高脂血症是SIOD患者的常见表型，但目前学界对这类表型的发生与发展机制尚不清楚。本研究证实，SMARCAL1在调控细胞脂质代谢过程中发挥关键作用。我们通过蛋白质组学方法发现，SMARCAL1可与血管生成素样蛋白3（Angptl3）——一种关键的脂蛋白调控因子——发生相互作用。细胞模型中SMARCAL1的缺失会导致甘油三酯（TGs）与脂肪酸（FAs）大量积累。小鼠体内的SMARCAL1基因敲除会显著升高血浆甘油三酯水平。令人意外的是，定位于细胞核的SMARCAL1会发生核质移位，并在过氧化物酶体处富集，在此处与Angptl3发生相互作用。这种核质穿梭机制可通过SMARCAL1调控的基因表达，对细胞脂质代谢进行调控，以响应细胞的生长状态。SMARCAL1基因的失活会降低脂肪酸代谢相关基因的表达水平，这表明SMARCAL1在脂质代谢调控中扮演关键角色。事实上，Angptl3介导的甘油三酯分配过程在很大程度上依赖于SMARCAL1的活性。这一结论进一步得到了两项相反的SMARCAL1单组织表达谱数据的支持：这两项表达谱分别与两个数量性状位点相关，而这两个位点与体重指数（body mass index）的关联存在差异。综上，SMARCAL1对细胞脂质代谢至关重要，而ANGPTL3调控的SMARCAL1活性可使细胞根据自身生长状态，调整甘油三酯的储存或消耗过程。