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Mechanisms of Berberine for the Treatment of Non-Alcoholic Fatty Liver Disease

小檗碱治疗非酒精性脂肪肝的机制

基本信息

批准号：
10046281
负责人：
HUIPING Rose ZHOU
金额：
--
依托单位：
VA VETERANS ADMINISTRATION HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-10-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046281
关键词：
Affect Alkaloids Animal Model Anti-Inflammatory Agents Apoptosis Asia Berberine Bile Acids Cholesterol Cholesterol Homeostasis Clinic Clinical Trials Communicable Diseases Complementary and alternative medicine Development Disease Disease Progression Dyslipidemias Epithelial Cells Equilibrium FDA approved Fatty acid glycerol esters Future Health Hepatic Hepatocyte HuR protein Hypoglycemia Immune Immune response Inflammation Inflammatory Inflammatory Response Insulin Resistance Interleukin-6 Intestinal permeability Isoquinolines Knock-out Lead Link Lipids Lipopolysaccharides Liver diseases Mediating Medicinal Herbs Medicine Metabolic Metabolic Diseases Metabolic syndrome MicroRNAs Modeling Molecular Natural Products Nucleotides Pathogenesis Pharmaceutical Preparations Pharmacology Plants Property Proteins RNA-Binding Proteins Reporting Research Role Saturated Fatty Acids Signal Pathway TNF gene Testing Therapeutic Agents Therapeutic Effect Untranslated RNA Veterans base bile acid metabolism biological adaptation to stress chronic liver disease clinical development cytokine endoplasmic reticulum stress gut microbiota in vivo intestinal barrier intestinal epithelium lipid metabolism long chain fatty acid macrophage metabolic endotoxemia military veteran non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutic intervention protective effect response systemic inflammatory response therapeutic evaluation therapeutically effective transcription factor CHOP western diet

项目摘要

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease, especially among US veterans. NAFLD is critically linked to inflammation, insulin resistance, dyslipidemia, and the metabolic syndrome. Recent advances in NAFLD and non-alcoholic steatohepatitis (NASH) studies indicate that gut microbiota exerts a significant role in the disease progression by affecting host metabolic balance and immune response. The “metabolic endotoxemia” and elevated circulating levels of lipopolysaccharide (LPS) due to disruption of intestinal barrier function and free long chain fatty acids (FFA) are implicated in the stimulation of systemic inflammation and insulin resistance, both of which are positively correlated with the development and progression of NAFLD. Although the mechanism by which LPS/FFA induce hepatic lipotoxicity is still not fully understood, LPS/FFA-induced expression of inflammatory cytokines such as TNF-  and activation of the endoplasmic reticulum (ER) stress signaling pathway, known as the unfolded protein response (UPR), are major contributors. Furthermore, micro-RNAs (miR), small noncoding RNAs (~22 nucleotides), have recently been found to be potent regulators of lipid and cholesterol metabolism. Alterations in miR expression have also been linked to LPS/FFA-induced inflammatory response, hepatic lipotoxicity and insulin resistance as well as disease progression of NAFLD in the clinic. Berberine (BBR), an isoquinoline alkaloid isolated from many medicinal herbs, has been used to treat various infectious disorders for more than 3,000 years in Asia. Numerous studies have shown that BBR has various pharmacological activities including anti-inflammatory, hypoglycemic and lipid-lowering effects. Importantly, BBR represents a novel cholesterol- lowering drug through a unique mechanism distinct from the current statin therapy. These studies strongly indicate that BBR is a promising natural therapeutic agent for NAFLD/NASH. However, the molecular mechanisms underlying BBR’s anti-inflammatory and lipid-lowering properties remain to be fully identified. We have demonstrated that BBR inhibits ER stress-mediated TNF- and IL-6 expression through regulating the RNA-binding protein (RBP) HuR in macrophages. Recent advances in miR research have identified specific panels of miRs as major regulators of inflammation, lipid metabolism and metabolic disorders, such as miR-155, miR-125a-5p, miR-33, miR-34a, and miR-122. In addition, it has been reported that BBR exerted protective effects against high fat Western diet (WD)-induced NAFLD/NASH via modulating gut microbiota and bile acid metabolism. Our preliminary studies also indicate that 1) BBR significantly inhibited WD-induced hepatic lipid accumulation and systemic inflammation in animal models; 2) BBR inhibited FFA-induced ER stress and lipid accumulation in hepatocytes; 3) BBR inhibited FFA-induced miR-34a expression in hepatocytes and LPS-induced miR-125a-5p expression in macrophages; 4) The expression of miR-34a was significantly down-regulated in C/EBP homologous protein (CHOP, a major player of ER stress-mediated apoptosis) knock out (CHOP-/-) primary hepatocytes; 5) BBR significantly reduced WD-induced increase of intestinal permeability; 6) ER stress- and LPS-induced suppression of intestinal epithelial cell renewal was rescued by deletion of the CHOP. Based on these observations, we HYPOTHESIZE that BBR inhibits WD- induced hepatic lipotoxicity by inhibiting ER stress and inflammatory response. The following two specific aims are proposed to test this hypothesis. Aim #1:To determine the mechanism by which BBR inhibits LPS/FFA-induced ER stress and the inflammatory response in hepatocytes and macrophages; Aim #2: To identify the mechanism by which BBR inhibits WD-induced hepatic lipotoxicity and further test the therapeutic effect of BBR on WD-induced hepatic lipotoxicity in a novel in vivo NAFLD/NASH model.

非酒精性脂肪性肝病（NAFLD）已成为最常见的慢性肝病，尤其是在美国退伍军人中。 NAFLD 与炎症、胰岛素抵抗、血脂异常和代谢综合征。 NAFLD 和非酒精性脂肪性肝炎 (NASH) 研究的最新进展表明肠道微生物群通过影响宿主代谢平衡在疾病进展中发挥重要作用和免疫反应。 “代谢性内毒素血症”和脂多糖循环水平升高（LPS）由于肠道屏障功能破坏而产生，而游离长链脂肪酸（FFA）则与刺激全身炎症和胰岛素抵抗，两者均与 NAFLD 的发生和进展。尽管 LPS/FFA 诱导肝损伤的机制脂毒性尚未完全了解，LPS/FFA 诱导炎症细胞因子（如 TNF-α）的表达  和内质网 (ER) 应激信号通路（称为未折叠蛋白）的激活响应（UPR），是主要贡献者。此外，微小 RNA (miR)、小非编码 RNA (~22 核苷酸），最近被发现是脂质和胆固醇代谢的有效调节剂。改动 miR 表达也与 LPS/FFA 诱导的炎症反应、肝脂毒性和胰岛素抵抗以及 NAFLD 在临床上的疾病进展。小檗碱 (BBR)，一种异喹啉从许多草药中分离出的生物碱已被用于治疗各种感染性疾病超过亚洲已有3000年历史。大量研究表明 BBR 具有多种药理活性，包括具有抗炎、降血糖、降脂作用。重要的是，BBR 代表了一种新型胆固醇- 通过与当前他汀类药物治疗不同的独特机制来降低药物浓度。这些研究强烈表明 BBR 是一种有前途的 NAFLD/NASH 天然治疗剂。然而，分子 BBR 抗炎和降脂特性的机制仍有待完全确定。我们已经证明，BBR 通过调节 ER 应激介导的 TNF-α 和 IL-6 表达来抑制巨噬细胞中的 RNA 结合蛋白 (RBP) HuR。 miR 研究的最新进展已经确定特定的 miR 组作为炎症、脂质代谢和代谢紊乱的主要调节因子，例如如 miR-155、miR-125a-5p、miR-33、miR-34a 和 miR-122。此外，据报道，BBR还发挥了通过调节肠道微生物群对高脂肪西方饮食 (WD) 诱发的 NAFLD/NASH 产生保护作用和胆汁酸代谢。我们的初步研究还表明1）BBR显着抑制WD诱导的动物模型中的肝脏脂质积累和全身炎症； 2) BBR抑制FFA诱导的ER 肝细胞内的应激和脂质积累； 3) BBR抑制FFA诱导的miR-34a表达肝细胞和 LPS 诱导巨噬细胞中 miR-125a-5p 表达； 4) miR-34a的表达量为 C/EBP 同源蛋白（CHOP，ER 应激介导的主要参与者）显着下调细胞凋亡）敲除（CHOP-/-）原代肝细胞； 5) BBR显着降低了WD引起的肠道通透性； 6) ER应激和LPS诱导的肠上皮细胞更新抑制通过删除 CHOP 来挽救。基于这些观察，我们假设 BBR 抑制 WD- 通过抑制内质网应激和炎症反应诱导肝脂毒性。具体有以下两个提出的目标是检验这一假设。目标#1：确定 BBR 抑制的机制 LPS/FFA诱导的ER应激以及肝细胞和巨噬细胞的炎症反应；目标#2：确定 BBR 抑制 WD 诱导的肝脂毒性的机制并进一步测试治疗效果在新型体内 NAFLD/NASH 模型中，BBR 对 WD 诱导的肝脂毒性的影响。