PDF(Pubmed)
Abstract：
Single-nucleotide polymorphisms in G protein-coupled receptor 180 (GPR180) are associated with hypertriglyceridemia. The aim of this study was to determine whether hepatic GPR180 impacts lipid metabolism. Hepatic GPR180 was knocked down using two approaches: Gpr180-specific short hairpin (sh)RNA carried by adeno-associated virus 9 (AAV9) and alb-Gpr180-/- transgene established by crossbreeding albumin-Cre mice with Gpr180flox/flox animals, in which Gpr180 was specifically knocked down in hepatocytes. Adiposity, hepatic lipid contents, and proteins related to lipid metabolism were analyzed. The effects of GPR180 on triglyceride and cholesterol synthesis were further verified by knocking down or overexpressing Gpr180 in Hepa1-6 cells. Gpr180 mRNA was upregulated in the liver of HFD-induced obese mice. Deficiency of Gpr180 decreased triglyceride and cholesterol contents in the liver and plasma, ameliorated hepatic lipid deposition in HFD-induced obese mice, increased energy metabolism, and reduced adiposity. These alterations were associated with downregulation of transcription factors SREBP1 and SREBP2, and their target acetyl-CoA carboxylase. In Hepa1-6 cells, Gpr180 knockdown decreased intracellular triglyceride and cholesterol contents, whereas its overexpression increased their levels. Overexpression of Gpr180 significantly reduced the PKA-mediated phosphorylation of substrates and consequent CREB activity. Hence, GPR180 might represent a novel drug target for intervention of adiposity and liver steatosis.
摘要：
G蛋白偶联受体180（GPR180）的单核苷酸多态性与高甘油三酯血症相关。这项研究的目的是确定肝GPR180是否影响脂质代谢。使用两种方法将肝GPR180敲低：腺相关病毒9（AAV9）携带的Gpr180特异性短发夹（sh）RNA和通过将白蛋白-Cre小鼠与Gpr180flox/flox动物杂交建立的alb-Gpr180-/-转基因，其中Gpr180在肝细胞中被特异性敲低。肥胖，肝脂质含量，分析与脂质代谢相关的蛋白质。通过在Hepa1-6细胞中敲低或过表达Gpr180，进一步验证了GPR180对甘油三酯和胆固醇合成的影响。Gpr180mRNA在HFD诱导的肥胖小鼠肝脏中上调。Gpr180的缺乏降低了肝脏和血浆中的甘油三酯和胆固醇含量，改善HFD诱导的肥胖小鼠的肝脏脂质沉积，增加能量代谢，减少肥胖。这些改变与转录因子SREBP1和SREBP2及其靶乙酰辅酶A羧化酶的下调有关。在Hepa1-6细胞中，Gpr180敲除降低细胞内甘油三酯和胆固醇含量，而它的过表达增加了它们的水平。Gpr180的过表达显著降低了PKA介导的底物磷酸化和随后的CREB活性。因此，GPR180可能是干预肥胖和肝脏脂肪变性的新药物靶标。
