Omega-3 fatty acids and the control of fatty liver disease

Omega-3 脂肪酸与脂肪肝疾病的控制

• 批准号: 9506774
• 负责人: DONALD B JUMP
• 金额: $ 33.08万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9506774
• 关键词: Attenuated; Benign; Biological Markers; Cells; Central obesity; Cirrhosis; Clinical; Coculture Techniques; Comorbidity; Culture Techniques; Diet; Disease remission; Docosahexaenoic Acids; Dyslipidemias; Epidemic; Erinaceidae; Event; FDA approved; Fatty Liver; Fatty acid glycerol esters; Female; Fibrosis; Foundations; Generations; Goals; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; Human; Hyperglycemia; Hypertension; Incidence; Inflammation; Link; Liver; Liver Fibrosis; Liver diseases; Mediating; Membrane Lipids; Metabolic; Metabolic syndrome; Molecular; Mono-S; Mus; Obesity; Omega-3 Fatty Acids; Onset of illness; Outcome; Pathology; Pathway interactions; Patients; Plasma; Positioning Attribute; Pre-Clinical Model; Prevalence; Prevention; Primary carcinoma of the liver cells; Public Health; Regulatory Pathway; Reporting; Research; Signal Pathway; Signal Transduction; Societies; Sucrose; Supplementation; Testing; Time; Transforming Growth Factor beta; attenuation; base; cell type; chronic liver disease; diabetic patient; in vivo; lipid metabolism; macrophage; male; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; notch protein; osteopontin; oxidized lipid; pre-clinical; preclinical study; prevent; response; stellate cell; western diet

Obese and type 2 diabetic (T2DM) patients have a high incidence of nonalcoholic fatty liver disease (NAFLD). NAFLD is a continuum of chronic liver diseases ranging from benign steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis and primary hepatocellular cancer (HCC). Because of its strong association with the obesity epidemic, NAFLD is rapidly becoming a major public health concern in western societies. Surprisingly, there are no FDA approved NAFLD therapies; and current therapies treat the co-morbidities associated with NAFLD, viz., obesity, hyperglycemia, dyslipidemia, & hypertension. Our focus is on prevention of NAFLD and stopping its progression to NASH. We developed a preclinical Ldlr-/- mouse model of western diet (WD)-induced NASH. High fat-high sucrose diets, like the WD, have been implicated in promoting the obesity epidemic. Our preclinical model recapitulates the features seen in the metabolic syndrome (MetS)-NASH patient, i.e., obesity, hyperglycemia, dyslipidemia, hepatosteatosis, systemic and hepatic inflammation & hepatic fibrosis. The key premise of this application is that there is a causal link between hepatic C20-22 ω3 PUFA content and the onset and progression of NASH. This premise is based on the following research from our lab: 1) WD induced NASH is associated with hepatic depletion of C20-22 ω3 PUFA and bioactive ω3 PUFA-derived oxidized lipids (oxylipins); findings that parallel recent reports on NASH patients; 2) repletion of hepatic C20-22 ω3 PUFA and oxylipins with docosahexaenoic acid (DHA, 22:6,ω3) supplementation prevents NASH and stops its progression; 3) New evidence shows that DHA attenuates WD-mediated induction of key NASH pathways [SREBP1, NFκB, TGFβ-Smad3, Notch, Hedgehog (Hh) and osteopontin (Opn)]; and 4) more New evidence shows that ω6-PUFA-derived, but not ω3-PUFA-derived, oxylipins augment TGFβ induction of a key fibrosis marker (smActin) in human hepatic stellate cells. Thus, DHA and its oxylipin derivatives regulate multiple NASH-linked pathways. We are well-positioned to uncover the metabolic and molecular basis for DHA-mediated suppression of NASH using our preclinical Ldlr -/- mouse model. Our goal is to provide the mechanistic foundation for the use of DHA in NASH therapy. We hypothesize that DHA attenuation of diet-induced NASH and fibrosis involves both direct and indirect mechanisms controlling major regulatory pathways (TGFβ, Notch, HH & Opn) linked to NASH. AIM 1 will use an in vivo time course approach to test the hypothesis that DHA will induce changes in hepatic membrane lipid composition and PUFA-derived oxylipins that precede changes in the expression/activity of signaling pathways linked to NASH & fibrosis. AIM 2 will test the hypothesis that PUFA & oxylipins act directly on isolated liver cells (hepatocytes, macrophage & stellate cells) to regulate signaling pathways (TGFβ, Notch, Hh & Opn) linked to NASH pathology.

肥胖和2型糖尿病（T2 DM）患者非酒精性脂肪肝（NAFLD）的发病率较高。NAFLD是一系列慢性肝病，从良性脂肪变性到非酒精性脂肪性肝炎（NASH）、肝硬化和原发性肝细胞癌（HCC）。由于其与肥胖流行的密切联系，NAFLD正在迅速成为西方社会的主要公共卫生问题。令人惊讶的是，没有FDA批准的NAFLD疗法;并且目前的疗法治疗与NAFLD相关的共病，即，肥胖、高血糖、血脂异常和高血压。我们的重点是预防NAFLD并阻止其进展为NASH。我们开发了西方饮食（WD）诱导的NASH的临床前Ldlr-/-小鼠模型。高脂肪高蔗糖饮食，如WD，已被牵连在促进肥胖流行。我们的临床前模型概括了在代谢综合征（MetS）-NASH患者中观察到的特征，即，肥胖、高血糖、血脂异常、脂肪肝、全身性和肝脏炎症以及肝纤维化。本申请的关键前提是肝脏C20-22 ω3 PUFA含量与NASH的发作和进展之间存在因果关系。这一假设基于本实验室的以下研究：1）WD诱导的NASH与肝脏C20-22 ω3 PUFA和ω3 PUFA衍生的生物活性氧化脂质的消耗有关（氧脂类）;与NASH患者的近期报告平行的发现; 2）肝脏C20-22 ω3 PUFA和二十二碳六烯酸氧脂类的补充（DHA，22：6，ω3）补充可预防NASH并阻止其进展; 3）新证据表明DHA可减弱WD介导的NASH关键通路[SREBP 1、NFκB、TGFβ-Smad 3、Notch、Hedgehog（Hh）和OPN（Opn）]的诱导;和4）更多的新证据表明，ω6-PUFA衍生的而非ω3-PUFA衍生的氧化脂质增强TGFβ对人肝星状细胞中关键纤维化标志物（smActin）的诱导。因此，DHA及其氧脂肽衍生物调节多种NASH相关途径。我们处于有利地位，可以使用我们的临床前Ldlr -/-小鼠模型来揭示DHA介导的NASH抑制的代谢和分子基础。我们的目标是为DHA在NASH治疗中的应用提供机制基础。我们假设DHA对饮食诱导的NASH和纤维化的减弱涉及控制与NASH相关的主要调节途径（TGFβ、Notch、HH和Opn）的直接和间接机制。AIM 1将使用体内时程方法来测试DHA将诱导肝膜脂质组成和PUFA衍生的氧化脂质的变化的假设，该变化先于与NASH和纤维化相关的信号传导途径的表达/活性的变化。目的2将测试PUFA和氧脂直接作用于分离的肝细胞（肝细胞、巨噬细胞和星状细胞）以调节与NASH病理学相关的信号通路（TGFβ、Notch、Hh和Opn）的假设。