Graduate Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley.
Arterioscler Thromb Vasc Biol. 2021 Dec;41(12):2866-2876. doi: 10.1161/ATVBAHA.121.316764. Epub 2021 Oct 7.
We measured the turnover rates of the LDLR (low-density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type 9) in mice by metabolic labeling with heavy water and mass spectrometry. Approach and Results: In liver of mice fed high-cholesterol diets, LDLR mRNA levels and synthesis rates were markedly lower with complete suppression of cholesterol synthesis and higher cholesterol content, consistent with the Brown-Goldstein model of tissue cholesterol homeostasis. We observed markedly lower PCSK9 mRNA levels and synthesis rates in liver and lower concentrations and synthesis rates in plasma. Hepatic LDLR half-life (t½) was prolonged, consistent with an effect of reduced PCSK9, and resulted in no reduction in hepatic LDLR content despite reduced mRNA levels and LDLR synthesis rates. These changes in PCSK9 synthesis complement and expand the well-established model of tissue cholesterol homeostasis in mouse liver, in that reduced synthesis and levels of PCSK9 counterbalance lower LDLR synthesis by promoting less LDLR catabolism, thereby maintaining uptake of LDL cholesterol into liver despite high intracellular cholesterol concentrations.
Lower hepatic synthesis and secretion of PCSK9, an SREBP2 (sterol response element binding protein) target gene, results in longer hepatic LDLR t½ in response to cholesterol feeding in mice in the face of high intracellular cholesterol content. PCSK9 modulation opposes the canonical lowering of LDLR mRNA and synthesis by cholesterol surplus and preserves LDLR levels. The physiological and therapeutic implications of these opposing control mechanisms over liver LDLR are of interest and may reflect subservience of hepatic cholesterol homeostasis to whole body cholesterol needs.
我们通过氘标记和质谱法测量了 LDLR（低密度脂蛋白受体）和 PCSK9（前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9）在小鼠中的周转率。
在喂食高胆固醇饮食的小鼠肝脏中，LDLR mRNA 水平和合成率明显降低，同时胆固醇合成完全受到抑制，胆固醇含量升高，这与组织胆固醇稳态的 Brown-Goldstein 模型一致。我们观察到肝脏中 PCSK9 mRNA 水平和合成率明显降低，血浆中 PCSK9 浓度和合成率降低。肝 LDLR 半衰期（t½）延长，这与 PCSK9 减少的作用一致，尽管 LDLR mRNA 水平和 LDLR 合成率降低，但肝 LDLR 含量没有减少。这些 PCSK9 合成的变化补充并扩展了小鼠肝脏组织胆固醇稳态的经典模型，即降低的 PCSK9 合成和水平通过促进 LDLR 分解代谢减少，从而在细胞内胆固醇浓度高的情况下，维持 LDL 胆固醇摄取进入肝脏。
在面对高细胞内胆固醇浓度时，肝脏中 PCSK9（一种 SREBP2 靶基因）的合成和分泌减少，导致 LDLR 的肝半衰期延长。PCSK9 调节与胆固醇过剩导致的 LDLR mRNA 和合成的经典降低作用相反，并维持 LDLR 水平。这些相反的肝脏 LDLR 控制机制的生理和治疗意义值得关注，并且可能反映了肝脏胆固醇稳态对全身胆固醇需求的从属关系。
