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: 9380211
• 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/9380211
• 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; 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)患者非酒精性脂肪性肝病(NAFLD)发生率高。NAFLD是从良性脂肪变性到非酒精性脂肪性肝炎(NASH)、肝硬变和原发性肝细胞癌(HCC)的一系列慢性肝病。由于与肥胖流行病密切相关，NAFLD正迅速成为西方社会的一个主要公共卫生问题。令人惊讶的是，没有FDA批准的NAFLD疗法；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并阻止其发展为NASH。我们建立了西方饮食(WD)诱导的NASH的临床前Ldlr-/-小鼠模型。高脂肪-高蔗糖饮食，如WD，被认为是促进肥胖流行的罪魁祸首。我们的临床前模型概括了代谢综合征(METS)-NASH患者的特征，即肥胖、高血糖、血脂异常、肝骨病、全身和肝脏炎症以及肝纤维化。这一应用的关键前提是肝脏C20-22、ω、3PUFA含量与NASH的发生发展之间存在因果联系。这一前提是基于我们实验室的以下研究：1)WD诱导的NASH与肝脏C20-22ω3多不饱和脂肪酸和生物活性ω3多不饱和脂肪酸衍生的氧化脂质(氧化脂质)的耗竭有关；与最近关于NASH患者的报道平行的发现；2)补充肝脏C20-22ω3多不饱和脂肪酸和氧脂与二十二碳六烯酸(DHA，22：6，ω3)补充预防NASH并阻止其进展；3)新证据表明DHA减弱了WD介导的关键NASH途径的诱导[SREBP1，NFκB，β-SMAD3，Notch，Hedgehog(H)和骨桥蛋白(OPN)]；4)更多的新证据表明，ω6-多不饱和脂肪酸而不是ω3-多不饱和脂肪酸衍生的氧化脂质可增强转化生长因子β对人肝星状细胞中一种关键的纤维化标志物(SMActin)的诱导。因此，DHA及其氧脂衍生物调节多条与NASH相连的通路。我们很好地利用我们的临床前Ldlr-/-小鼠模型来揭示DHA介导的抑制NASH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，饮食诱导的NASH和纤维化的DHA的减轻涉及控制与NASH相关的主要调控途径(转化生长因子β、Notch、HH和OPN)的直接和间接机制。目的1将采用体内时程方法检验DHA将导致肝膜脂质成分和多不饱和脂肪酸衍生的氧脂发生变化的假设，这些变化先于与NASH和纤维化相关的信号通路的表达/活性的变化。目的2验证多不饱和脂肪酸和氧化脂质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病理相关的信号通路(转化生长因子β、Notch、HH和OPN)的假说。