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: 10474511
• 负责人: SARAH Louise BOOTH
• 金额: $ 47.53万
• 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/10474511
• 关键词: 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; Germ Lines; Goals; Golgi Apparatus; Grant; Hepatic; Histologic; Homeostasis; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA reductase; Incidence; Injury; Intestines; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; LDL Cholesterol Lipoproteins; Light; Liver; Mediating; Membrane; Metabolism; Missense Mutation; Modality; Morphology; Mus; Muscle; Mutation; Myocardial Infarction; Myopathy; Nuclear Receptors; Outcome; Pancreas; Pathway interactions; Patients; Pharmacology; 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; cholesterol control; clinical effect; farnesyl pyrophosphate; geranylgeranyl pyrophosphate; insight; isoprenoid; knock-down; knockout gene; mevalonate; mutant; 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前转移酶结构蛋白1（UBIAD1）使用异胰醇异丙烷基凝集苷酸（GGPP）（GGPP）合成一种称为梅纳甲喹酮-4（MK-4）的维生素K的形式。 UbiAD1是多功能的，如人Ubiad1与Schnyder角膜营养不良（SCD）的突变的关联所示。这种罕见的常染色体显性眼病的特征是由于胆固醇的异常积累而进行性角膜衰弱。我们的研究表明，固醇导致UbiAD1结合内质网（ER）置换的HMG COA还原酶（HMGCR），胆固醇合成的速率限制酶和必需的非甾体类异型类别，包括法尼吡啶类吡磷酸盐，GGPP，MK-4，UB4，UBIQUINON，和ubiquiquiquin。固醇诱导的泛素化是由GGPP增强的HMGCR的ER相关降解（ERAD）的强制性，并且构成了一种反馈控制酶的机制。 GGPP阻断了固醇诱导的UBIAD1与HMGCR的结合，从而增强其ERAD并允许ubiAD1的ER到高尔基体转运。 UBIAD1的SCD相关突变体抵抗GGPP诱导的HMGCR位移，并在ER中保持隔离以抑制ERAD，这有助于增强的合成和胆固醇的细胞内积累。试图在小鼠中进行基因敲除研究，以阐明UbiAD1在MK-4组织特异性分布中的作用，这仍然是维生素K生物学中的主要未解决的问题。然而，UbiAD1的纯合种系缺失引起胚胎致死性。最近，我们在表达抗泛素化的HMGCR的小鼠中产生了UBIAD1的纯合删除，这意味着与UbiAD1缺乏相关的胚胎致死性是HMGCR的增强而导致的，这是由于HMGCR的增强并耗尽了Mevalonate代谢物与Mk-4的巨型代谢相关。 ERAD和MK-4的合成通过追求以下具体目的：1）探索GGPP介导的ubiAD介导的感觉在调节HMGCR ERAD和肝脏代谢中的作用； 2）确定UBIAD1介导的MK-4的合成对骨骼肌稳态的贡献； 3）在胰腺生存和功能中确立ubiAD1的作用； 4）检查UbiAD1在肠形态和功能中的作用。 PI的合并努力（在胆固醇代谢（Debose-Boyd）和维生素K生物学（Booth）的基础机制方面具有互补的专业知识，将导致发现由MK-4调节的组织特异性途径/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，汀类药物是降低血浆LDL-胆固醇并降低心血管疾病（CVD）的发生率的靶标。然而，他汀类药物会引起导致HMGCR积累的反应，从而钝其临床作用。这一增加的一部分是由于UBIAD1介导的HMGCR ERAD抑制。我们的研究可能会暴露于GGPP的UBIAD1-介导感应，这是防止他汀类药物诱导的HMGCR积累，汀类药物疗效提高并最终降低CVD和心脏病发作的发生率。