Investigating Synthetic Ligands for the Treatment of NASH

研究治疗 NASH 的合成配体

• 批准号: 8993599
• 负责人: Kristine Griffett
• 金额: $ 6万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-05 至 2017-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8993599
• 关键词: Adverse effects; Agonist; Atherosclerosis; Carbohydrates; Cholesterol; Development; Diabetes Mellitus; Diet; Disease; Drug Targeting; Fatty Liver; Gene Expression; Genes; Genetic Models; Hepatic; Inflammation; LXRalpha protein; Life; Ligands; Lipids; Liver; Liver X Receptor; Liver diseases; Malignant Neoplasms; Mediating; Metabolic Diseases; Metabolic Pathway; Metabolism; Morbidity - disease rate; Mus; Nuclear Hormone Receptors; Nuclear Receptors; Obese Mice; Obesity; Orphan; Pathology; Pathway interactions; Pharmacologic Substance; Physiology; Play; Process; Proteins; RXR; Regulation; Role; Steatohepatitis; Testing; Therapeutic; Work; base; fatty acid oxidation; lipid biosynthesis; lipid metabolism; liver metabolism; member; mortality; mouse model; new therapeutic target; nonalcoholic steatohepatitis; novel; public health relevance; sensor; tool

 DESCRIPTION (provided by applicant): Metabolic diseases, associated with abnormal processing of proteins, carbohydrates, and lipids, are the cause of significant morbidity and mortality. The nuclear receptors, liver X receptor a, and -ß (LXRa and LXRß), were originally identified as orphan members of the nuclear receptor (NR) superfamily that function as heterodimers with the retinoid X receptor (RXR). Both LXRa and LXRß play important roles in cholesterol physiology and lipid metabolism, and have been implicated in the pathology of several diseases, including athereosclerosis, cancer, and obesity. Detailed examination of mice deficient in LXRa have revealed a significant amount of information regarding its role in regulating metabolic pathways, including lipid metabolism. Potential pharmacological roles of LXR in metabolism have been identified using synthetic agonists, however our focus for this study is the use of inverse agonists in the treatment of fatty liver diseases. We have identified a novel synthetic LXR inverse agonist that displays the ability to specifically suppress LXR target gene expression specifically in the liver, thus having the potential to suppress steatohepatitis. The long-term objective is to use these compounds as tools to study the effects of synthetic LXR ligands on diseases of the liver. We hypothesize that LXR inverse agonists can suppress the effects Fatty Liver Diseases in mouse models. Our hypothesis will be tested in the following specific aims: Specific Aim 1 will examine the mechanism(s) by which SR9238 effects LXR-mediated lipogenesis, inflammation, and cholesterol regulation; Specific Aim 2 will evaluate the potential for SR9238 as a therapeutic in Non- Alcoholic Steatohepatitis (NASH) in mouse models of the disease. Ligand-regulated nuclear hormone receptors have been definitively shown to be effective targets for the development of pharmaceuticals. We predict that these studies will provide the basis for novel therapeutics targeting LXR for the treatment of fatty live diseases and potentially other metabolic disorders.

 描述（由申请人提供）：与蛋白质、碳水化合物和脂质的异常加工相关的代谢性疾病是导致显着发病和死亡的原因。 LXRa 和 LXRß 最初被鉴定为核受体 (NR) 超家族的孤儿成员，与类视黄醇 X 受体 (RXR) 一起作为异二聚体发挥作用。对 LXRa 缺陷小鼠的详细检查揭示了有关其在调节代谢途径（包括脂质代谢）中的作用的大量信息。 LXR 在代谢中的潜在药理学作用已通过合成激动剂确定，但本研究的重点是使用反向激动剂治疗脂肪肝疾病。 新型合成 LXR 反向激动剂，具有特异性抑制肝脏中 LXR 靶基因表达的能力，因此具有抑制脂肪性肝炎的潜力。长期目标是使用这些化合物作为工具来研究合成 LXR 配体对肝脏的影响。我们得出结论，LXR 反向激动剂可以抑制小鼠模型中脂肪肝疾病的影响。我们的假设将在以下具体目标中进行检验：具体目标 1 将检查SR9238 影响 LXR 介导的脂肪生成、炎症和胆固醇调节的机制；具体目标 2 将评估 SR9238 在配体调节的核疾病模型中作为非酒精性脂肪性肝炎 (NASH) 治疗的潜力。激素受体已被明确证明是药物开发的有效靶标，我们预测这些研究将为治疗脂肪性肝病的新型疗法奠定基础。其他代谢紊乱。

项目成果

Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists.

肠道限制的 LXR 反向激动剂的抗高血脂活性。

• DOI: 10.1021/acschembio.2c00057
• 发表时间: 2022-04-13
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: K. Griffett;Matthew E. Hayes;Gonzalo Bedia;K. Appourchaux;Ryan S;ers;ers;Michael P Boeckman;Thomas Koelblen;Jinsong Zhang;I. Schulman;Bahaa Elgendy;T. Burris
• 通讯作者: T. Burris

Inhibition of Hepatotoxicity by a LXR Inverse Agonist in a Model of Alcoholic Liver Disease.

LXR 反向激动剂在酒精性肝病模型中抑制肝毒性。

• DOI: 10.1021/acsptsci.8b00003
• 发表时间: 2018-07-25
• 期刊: ACS pharmacology & translational science
• 作者: Monideepa Sengupta;K. Griffett;Colin A. Flaveny;T. Burris
• 通讯作者: T. Burris

The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis.

LXR 反向激动剂 SR9238 可抑制非酒精性脂肪性肝炎模型中的纤维化。

• 发表时间: 2015-04
• 影响因子: 8.1
• 作者: Griffett, Kristine;Welch, Ryan D;Flaveny, Colin A;Kolar, Grant R;Neuschwander;Burris, Thomas P
• 通讯作者: Burris, Thomas P

REV-ERB agonism improves liver pathology in a mouse model of NASH.

REV-ERB 激动可改善 NASH 小鼠模型的肝脏病理学。

• 发表时间: 2020
• 影响因子: 3.7
• 作者: Griffett, Kristine;Bedia;Elgendy, Bahaa;Burris, Thomas P
• 通讯作者: Burris, Thomas P

A two-hit model of alcoholic liver disease that exhibits rapid, severe fibrosis.

酒精性肝病的二次打击模型，表现出快速、严重的纤维化。

• 发表时间: 2021
• 影响因子: 3.7
• 作者: Sengupta, Monideepa;Abuirqeba, Suomia;Kameric, Amina;Cecile;Chatterjee, Arindam;Griffett, Kristine;Burris, Thomas P;Flaveny, Colin A
• 通讯作者: Flaveny, Colin A