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异戊烯基转移酶结构域蛋白-1（UBIAD 1）使用非固醇类异戊二烯香叶基香叶基焦磷酸（GGpp）合成一种称为甲基萘醌-4（MK-4）的维生素K形式。UBIAD 1是多功能的，如人UBIAD 1中的突变与施奈德角膜营养不良（SCD）的关联所示。这种罕见的常染色体显性遗传眼病的特征是由于胆固醇的异常积累导致的进行性角膜混浊。我们的研究表明，甾醇导致UBIAD 1结合内质网（ER）定位的HMG CoA还原酶（HMGCR），这是合成胆固醇和必需的非甾醇类异戊二烯（包括焦磷酸法呢酯、GGpp、MK-4、泛醌和多萜醇）的限速酶。甾醇诱导的泛素化对于HMGCR的ER相关降解（ERAD）是必需的，其被GGpp增强，并且构成了酶的反馈控制的一种机制。GGpp阻断固醇诱导的UBIAD 1与HMGCR的结合，这增强了其ERAD并允许UBIAD 1的ER至高尔基体转运。UBIAD 1的SCD相关突变体抵抗GGpp诱导的HMGCR置换，并保持在ER中隔离以抑制ERAD，这有助于胆固醇的合成和细胞内积累增强。在小鼠中的基因敲除研究试图阐明UBIAD 1在MK-4的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，Ubiad 1的纯合子生殖系缺失导致胚胎死亡。我们最近在表达泛素化抗性HMGCR的敲入小鼠中产生了Ubiad 1的纯合缺失，这意味着与Ubiad 1缺陷相关的胚胎致死性是由HMGCR的ERAD增强和与MK- 4不同的甲羟戊酸代谢物的消耗引起的。我们现在将通过追求以下特定目标来阐明UBIAD 1在调节HMGCR ERAD和MK-4合成中的组织特异性作用：1）探索UBIAD 1介导的GGpp传感在肝脏中调节HMGCR ERAD和甲羟戊酸代谢中的作用; 2）确定UBIAD 1介导的MK-4合成对骨骼肌稳态的贡献; 3）确定UBIAD 1在胰腺生存和功能中的作用;和4）检查UBIAD 1在肠的形态和功能中的作用。在胆固醇代谢（DeBose-Boyd）和维生素K生物学（Booth）调节机制方面具有互补专业知识的PI的共同努力将导致发现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是他汀类药物的靶点，他汀类药物是广泛使用的降低血浆LDL-胆固醇和降低心血管疾病（CVD）发病率的药物。然而，他汀类药物引发的反应导致HMGCR的积累，这削弱了他们的临床效果。这种增加的部分原因是UBIAD 1介导的HMGCR ERAD抑制。我们的研究可能揭示UBIAD 1介导的GGpp传感作为治疗的靶点，可预防他汀类药物诱导的HMGCR蓄积，增加他汀类药物疗效，并最终降低CVD和心脏病发作的发生率。