Liver X receptor beta is the dominant LXR subtype in skeletal muscle

Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRα and LXRβ subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRα and LXRβ knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRα KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRβ KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRα KO mice, but not LXRβ KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRβ in skeletal muscle. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRa and LXRb knockout (KO) mice were established. Sixteen samples were examined. Half the samples were treated with the unselective LXR agonist T0901317.

肝X受体（Liver X Receptors, LXRs）是调控胆固醇、脂质与葡萄糖代谢的关键调节因子，目前已在肝脏、巨噬细胞及脂肪组织中得到广泛研究。然而，其在骨骼肌中的作用尚未完全阐明，且LXRα与LXRβ两种亚型在骨骼肌内的具体功能角色目前仍属未知。为探究各受体亚型的重要性，本研究构建了源自野生型（wild type, WT）、LXRα基因敲除（knockout, KO）及LXRβ基因敲除小鼠的肌管培养体系。本研究结果显示，在源自野生型及LXRα基因敲除小鼠的肌管中，经非选择性肝X受体激动剂T0901317处理后，固醇调节元件结合转录因子1（SREBF1）、脂肪酸合酶（FASN）、硬脂酰辅酶A去饱和酶1（SCD1）及ATP结合盒转运蛋白A1（ABCA1）等肝X受体经典靶基因的mRNA水平均显著升高。但在源自LXRβ基因敲除小鼠的肌管中，经T0901317处理后，上述靶基因的表达仅出现轻微变化。通过Affymetrix NuGO基因芯片阵列开展的基因表达分析表明，除经典的已知肝X受体靶基因外，骨骼肌内受肝X受体调控的其他基因寥寥无几。此外，使用放射性标记底物进行的功能实验证实，在源自野生型及LXRα基因敲除小鼠的肌管中，T0901317处理可提升脂肪生成能力及载脂蛋白A1依赖性胆固醇流出水平，而在LXRβ基因敲除小鼠的肌管中则无此效应。本研究数据表明，肝X受体介导的脂肪生成效应以及肝X受体刺激的胆固醇流出过程，在骨骼肌中主要通过LXRβ亚型实现。为探究各受体亚型的重要性，本研究构建了源自野生型、LXRα及LXRβ基因敲除小鼠的肌管培养体系，共检测16份样本，其中半数样本经非选择性肝X受体激动剂T0901317处理。