Significance of UBIAD1 in Regulation of HMG CoA Reductase Degradation, Mevalonate Metabolism, and Menaquinone-4 Synthesis

UBIAD1 在调节 HMG CoA 还原酶降解、甲羟戊酸代谢和 Menaquinone-4 合成中的意义

• 批准号: 10626858
• 负责人: SARAH Louise BOOTH
• 金额: $ 47.29万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626858
• 关键词: Acceleration; Acinar Cell; Adult; Binding; Biology; Blood; Cardiovascular Diseases; Cause of Death; Cells; Cholesterol; Cholesterol Homeostasis; Clinical; Cornea; Coronary Arteriosclerosis; Cultured Cells; Dimethylallyltranstransferase; Diphosphates; Disease; Dolichol; Drug Prescriptions; Embryo; Endoplasmic Reticulum; Enzymes; Exhibits; Eye diseases; Feedback; Functional disorder; Goals; Golgi Apparatus; Grant; Hepatic; Histologic; Homeostasis; Human; Hydroxymethylglutaryl-CoA reductase; Incidence; Injury; Intestines; Knock-in Mouse; Knock-out; Knockout Mice; LDL Cholesterol Lipoproteins; Liver; Mediating; Membrane; Metabolism; Missense Mutation; Modality; Morphology; Mus; Muscle; Mutation; Myocardial Infarction; Myopathy; Nuclear Receptors; Outcome; Pancreas; Pathway interactions; Patients; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Plasma; Process; Proteins; Reaction; Regulation; Reporting; Resistance; Role; Schnyder corneal dystrophy; Site; Skeletal Muscle; Sterols; Tissues; Ubiquinone; Ubiquitination; Vitamin K; Vitamin K 2; Xenobiotics; autosome; cholesterol control; clinical effect; farnesyl pyrophosphate; geranylgeranyl pyrophosphate; inhibitor; insight; isoprenoid; knock-down; knockout gene; mevalonate; mutant; pharmacologic; pregnane X receptor; prevent; protein degradation; receptor binding; response; sensor; targeted treatment

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) uses the nonsterol isoprenoid geranylgeranyl pyrophosphate (GGpp) to synthesize a form of vitamin K called menaquinone-4 (MK-4). UBIAD1 is multifunctional as indicated by the association of mutations in human UBIAD1 with Schnyder corneal dystrophy (SCD). This rare autosomal dominant eye disease is characterized by progressive corneal opacification owing to abnormal accumulation of cholesterol. Our studies revealed that sterols cause UBIAD1 to bind endoplasmic reticulum (ER)-localized HMG CoA reductase (HMGCR), the rate-limiting enzyme in synthesis of cholesterol and essential nonsterol isoprenoids including farnesyl pyrophosphate, GGpp, MK-4, ubiquinone, and dolichol. Sterol- induced ubiquitination is obligatory for ER-associated degradation (ERAD) of HMGCR that is augmented by GGpp and constitutes one mechanism for feedback control of the enzyme. GGpp blocks sterol-induced binding of UBIAD1 to HMGCR, which enhances its ERAD and permits ER-to-Golgi transport of UBIAD1. SCD- associated mutants of UBIAD1 resist GGpp-induced displacement from HMGCR and remain sequestered in the ER to inhibit ERAD, which contributes to enhanced synthesis and intracellular accumulation of cholesterol. Gene knockout studies in mice were attempted to elucidate the role of UBIAD1 in tissue-specific distribution of MK-4, which remains a major unresolved question in vitamin K biology. However, homozygous germ-line deletion of Ubiad1 caused embryonic lethality. We recently generated homozygous deletion of Ubiad1 in knock- in mice expressing ubiquitination-resistant HMGCR, which implies embryonic lethality associated with Ubiad1 deficiency results from enhanced ERAD of HMGCR and depletion of mevalonate metabolites distinct from MK- 4. We will now elucidate tissue-specific roles of UBIAD1 in regulating HMGCR ERAD and MK-4 synthesis by pursuing the following Specific Aims: 1) Explore role of UBIAD1-mediated sensing of GGpp in regulation of HMGCR ERAD and mevalonate metabolism in the liver; 2) Determine contribution of UBIAD1-mediated synthesis of MK-4 to skeletal muscle homeostasis; 3) Establish roles for UBIAD1 in pancreatic subsistence and function; and 4) Examine role of UBIAD1 in morphology and function of the intestine. Combined efforts of the PIs, who have complementary expertise in mechanisms underlying regulation of cholesterol metabolism (DeBose-Boyd) and vitamin K biology (Booth), will lead to discovery of tissue-specific pathways/processes modulated by MK-4. In addition, these studies will have immediate clinical implications. HMGCR is the target of statins, widely prescribed drugs that lower plasma LDL-cholesterol and reduce incidence of cardiovascular disease (CVD). However, statins trigger responses that cause accumulation of HMGCR, which blunts their clinical effects. Part of this increase results from UBIAD1-mediated inhibition of HMGCR ERAD. Our studies may expose UBIAD1-mediating sensing of GGpp as a target of therapies that prevent statin-induced accumulation of HMGCR, increasing statin efficacy and ultimately reducing incidence of CVD and heart attacks.

UbiA-异戊基转移酶结构域包含蛋白-1(UBIAD1)利用非甾体类异戊二烯基香叶基焦磷酸(GGPP)合成一种形式的维生素K，称为Menaquinone-4(MK-4)。人类UBIAD1突变与Schnyder角膜营养不良(SCD)的相关性表明，UBIAD1是多功能的。这种罕见的常染色体显性遗传性眼病的特征是由于胆固醇的异常积聚而导致进行性角膜混浊。我们的研究表明，甾醇导致UBIAD1结合内质网(ER)定位的HMG CoA还原酶(HMGCR)，HMGCR是合成胆固醇和必需的非甾醇异戊二烯类化合物的限速酶，包括法尼基焦磷酸、GGPP、MK-4、泛醌和二苯二酚。类固醇诱导的泛素化是HMGCR内质网相关降解(ERAD)所必需的，GGPP增强了ERAD，并构成了该酶的反馈控制机制。GGPP阻断固醇诱导的UBIAD1与HMGCR的结合，从而增强其ERAD，并允许UBIAD1从ER到高尔基体的转运。UBIAD1的SCD相关突变体可以抵抗GGPP诱导的HMGCR置换，并保持在内质网中以抑制ERAD，从而促进胆固醇的合成和细胞内积累。小鼠的基因敲除研究试图阐明UBIAD1在MK-4组织特异性分布中的作用，这仍然是维生素K生物学中一个尚未解决的主要问题。然而，Ubiad1的纯合子胚系缺失会导致胚胎死亡。我们最近在表达泛素化抗性HMGCR的敲入小鼠中发现了Ubiad1的纯合子缺失，这意味着与Ubiad1缺乏相关的胚胎死亡与Ubiad1缺乏相关，这是由于HMGCR的ERAD增强和MK-4代谢物的耗竭所致。我们现在将通过追求以下特定目的来阐明UBIAD1在调节HMGCR ERAD和MK-4合成中的组织特异性作用：1)探讨UBIAD1介导的GGPP在肝脏调节HMGCR ERAD和甲戊酸代谢中的作用；2)确定UBIAD1介导的MK-4合成对骨骼肌内稳态的贡献；3)建立UBIAD1在胰腺生存和功能中的作用；4)检测UBIAD1在肠道形态和功能中的作用。PIs在胆固醇代谢的基础调控机制(DeBose-Boyd)和维生素K生物学(Booth)方面具有互补的专业知识，他们的共同努力将导致发现受MK-4调控的组织特有的途径/过程。此外，这些研究将具有直接的临床意义。HMGCR是他汀类药物的靶标，他汀类药物是广泛使用的降低血浆低密度脂蛋白-胆固醇和降低心血管疾病(CVD)发生率的药物。然而，他汀类药物会引发反应，导致HMGCR积聚，从而削弱其临床效果。这种增加的部分原因是UBIAD1介导的对HMGCR ERAD的抑制。我们的研究可能揭示UBIAD1介导的GGPP传感是预防他汀类药物诱导的HMGCR积聚、增加他汀类药物的疗效并最终降低心血管疾病和心脏病发作的治疗目标。