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: 9903289
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903289
• 关键词: Attenuated; Benign; Biological Markers; Cells; Central obesity; Cirrhosis; Clinical; Coculture Techniques; Culture Techniques; Diet; Disease remission; Docosahexaenoic Acids; Dyslipidemias; 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; Mus; Obesity; Obesity Epidemic; 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; Type 2 diabetic; attenuation; base; cell type; chronic liver disease; comorbidity; 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 (T2DM) 患者非酒精性脂肪肝 (NAFLD) 的发病率很高，NAFLD 是一系列慢性肝病，包括良性脂肪变性、非酒精性脂肪性肝炎 (NASH)、肝硬化和原发性肝细胞癌 (HCC)。由于 NAFLD 与肥胖流行密切相关，NAFLD 正迅速成为西方社会的主要公共卫生问题。令人惊讶的是，目前尚无 FDA 批准的 NAFLD 疗法；而目前的疗法可治疗与 NAFLD 相关的并发症，即肥胖、高血糖、血脂异常和高血压。西方饮食 (WD) 诱导的 NASH 临床前 Ldlr-/- 小鼠模型，如 WD，与促进 NASH 有关。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、肝脂肪变性、全身性和肝脏炎症以及肝纤维化。该应用的关键前提是存在。肝脏 C20-22 ω3 PUFA 含量与 NASH 的发生和进展之间的因果关系这一前提基于以下研究。来自我们实验室的研究结果：1) WD 诱导的 NASH 与肝脏 C20-22 ω3 PUFA 和生物活性 ω3 PUFA 衍生的氧化脂质（氧脂素）的消耗有关；2) 肝脏 C20-22 ω3 的补充与最近的研究结果相似； PUFA 和氧脂素与二十二碳六烯酸 (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 介导的关键 NASH 通路 [SREBP1、NFκB、TGFβ-Smad3、Notch、Hedgehog (Hh) 和骨桥蛋白 (Opn)]；新证据表明，源自 ω6-PUFA 的氧脂素（而非源自 ω3-PUFA 的氧脂素）可增强 TGFβ 对关键纤维化的诱导作用因此，DHA 及其氧脂质衍生物调节多种 NASH 相关途径，我们有能力利用我们的临床前 Ldlr -/- 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，我们发现 DHA 可以减轻饮食引起的 NASH 和纤维化。控制与 NASH AIM 1 相关的主要调节途径（TGFβ、Notch、HH 和 Opn）的直接和间接机制将使用体内时间过程方法来检验 DHA 会诱导肝膜脂质成分和 PUFA 衍生的氧脂质发生变化的假设。在与 NASH 和纤维化相关的信号通路的表达/活性发生变化之前，AIM 2 将检验 PUFA 和氧脂质直接作用于分离的肝细胞（肝细胞、巨噬细胞和肝细胞）的假设。星状细胞）调节与 NASH 病理相关的信号通路（TGFβ、Notch、Hh 和 Opn）。

项目成果

Omega-3 fatty acids and nonalcoholic fatty liver disease in adults and children: where do we stand?

Omega-3 脂肪酸与成人和儿童非酒精性脂肪肝：我们的立场如何？

• DOI: 10.1097/mco.0000000000000539
• 发表时间: 2019-03-01
• 期刊: Current Opinion in Clinical Nutrition and Metabolic Care
• 影响因子: 3.1
• 作者: Melinda H Spooner;D. Jump
• 通讯作者: D. Jump

Time course of western diet (WD) induced nonalcoholic steatohepatitis (NASH) in female and male Ldlr-/- mice.

西方饮食 (WD) 诱导雌性和雄性 Ldlr-/- 小鼠非酒精性脂肪性肝炎 (NASH) 的时间进程。

• 发表时间: 2023
• 影响因子: 3.7
• 作者: Spooner, Melinda H;Garcia;Apperson, K Denise;Löhr, Christiane V;Jump, Donald B
• 通讯作者: Jump, Donald B

Thermoneutral housing attenuates premature cancellous bone loss in male C57BL/6J mice.

热中性外壳可减轻雄性 C57BL/6J 小鼠的过早松质骨丢失。

• 发表时间: 2019-11
• 影响因子: 2.9
• 作者: Martin, Stephen A;Philbrick, Kenneth A;Wong, Carmen P;Olson, Dawn A;Branscum, Adam J;Jump, Donald B;Marik, Charles K;DenHerder, Jonathan M;Sargent, Jennifer L;Turner, Russell T;Iwaniec, Urszula T
• 通讯作者: Iwaniec, Urszula T

Supplementing Ca salts of soybean oil to late-gestating beef cows: impacts on performance and physiological responses of the offspring.

向妊娠晚期肉牛补充大豆油钙盐：对后代生产性能和生理反应的影响。

• 发表时间: 2020-08-01
• 影响因子: 3.3
• 作者: Brandão, Alice Poggi;Cooke, Reinaldo F;Schubach, Kelsey M;Rett, Bruna;Souza, Osvaldo A;Schachtschneider, Christopher L;Perry, George A;Arispe, Sergio A;Jump, Donald B;Pohler, Ky G;Bohnert, David W;Marques, Rodrigo S
• 通讯作者: Marques, Rodrigo S