Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), 225 South Chongqing Road, Shanghai 200025, China.
J Hepatol. 2011 Aug;55(2):445-52. doi: 10.1016/j.jhep.2010.11.022. Epub 2010 Dec 22.
BACKGROUND & AIMS: Excess dietary fat can cause hepatic steatosis, which can progress into severe liver disorders including steatohepatitis and cirrhosis. Steroid receptor coactivator-3 (SRC-3), a member of the p160 coactivator family, is reported as a key regulator of adipogenesis and energy homeostasis. We sought to determine the influence of SRC-3 on hepatic steatosis and the mechanism beneath.
The influence of siRNA-mediated SRC-3 silencing on hepatic lipid accumulation was assessed in HepG2 cells. The molecular mechanism of SRC-3 regulation of hepatic lipid metabolism was also studied. Moreover, the effect of SRC-3 ablation on hepatic steatosis was examined in SRC-3 deficient mice.
In this study, we report that SRC-3 ablation reduces palmitic acid-induced lipid accumulation in HepG2 cells. Moreover, deletion of SRC-3 ameliorates hepatic steatosis and inflammation response in mice fed a high fat diet (HFD). These metabolic improvements can presumably be explained by the reduction in chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) expression and the subsequent elevation in peroxisome proliferator-activated receptor α (PPARα) level. At the molecular level, SRC-3 interacts with retinoic receptor α (RARα) to activate COUP-TFII expression under all-trans retinoic acid (ARTA) treatment.
These findings indicate a crucial role for SRC-3 in regulating hepatic lipid metabolism and provide the possible novel inner mechanisms.
过量的膳食脂肪可导致肝脂肪变性，进而发展为严重的肝脏疾病，包括脂肪性肝炎和肝硬化。类固醇受体共激活因子-3（SRC-3）是 p160 共激活因子家族的一员，被报道为脂肪生成和能量稳态的关键调节因子。我们旨在确定 SRC-3 对肝脂肪变性的影响及其潜在机制。
用 siRNA 介导的 SRC-3 沉默法评估 SRC-3 对 HepG2 细胞中肝脂质积累的影响。还研究了 SRC-3 调节肝脂质代谢的分子机制。此外，在 SRC-3 缺陷小鼠中检测了 SRC-3 缺失对肝脂肪变性的影响。
在这项研究中，我们报告 SRC-3 缺失可减少棕榈酸诱导的 HepG2 细胞中的脂质积累。此外，SRC-3 缺失可改善高脂肪饮食喂养的小鼠的肝脂肪变性和炎症反应。这些代谢改善可能归因于鸡卵清蛋白上游启动子转录因子 II（COUP-TFII）表达的减少和随后过氧化物酶体增殖物激活受体 α（PPARα）水平的升高。在分子水平上，SRC-3 在全反式视黄酸（ATRA）处理下与维甲酸受体 α（RARα）相互作用以激活 COUP-TFII 的表达。
这些发现表明 SRC-3 在调节肝脂质代谢中起关键作用，并提供了可能的新的内在机制。
