The Role of GPR120 and Omega-3 Fatty Acids in Steatosis and Systemic Inflammation

GPR120 和 Omega-3 脂肪酸在脂肪变性和全身炎症中的作用

• 批准号: 8629544
• 负责人: Sarah J Carlson
• 金额: $ 5.57万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629544
• 关键词: Acids; Address; Adipose tissue; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Carbohydrates; Child; Cholestasis; Cirrhosis; Control Groups; Development; Diagnosis; Diet; Docosahexaenoic Acids; Emulsions; Exhibits; Failure; Fatty acid glycerol esters; Fibrosis; Fish Oils; G-Protein-Coupled Receptors; Goals; Health Benefit; Human; In Vitro; Individual; Infant; Inflammation; Inflammatory; Injection of therapeutic agent; Insulin Resistance; Intestines; Intravenous; Knock-out; Knockout Mice; Laboratories; Leukotrienes; Life; Lipids; Lipopolysaccharides; Liver; Liver diseases; Mediating; Modeling; Molecular; Mus; Normal saline; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Parenteral Nutrition; Pathway interactions; Patients; Peripheral; Phytosterols; Play; Prevention; Property; Prostaglandins; Randomized; Rodent; Role; Saline; Series; Serum; Solutions; Soybean Oil; Staging; Syndrome; TNF gene; Tail; Testing; Tissues; Wild Type Mouse; base; cytokine; feeding; in vivo; inflammatory marker; liver injury; nutrition; prevent; prostaglandin E3; protective effect; public health relevance; receptor

DESCRIPTION (provided by applicant): Parenteral nutrition (PN) has been credited with saving the lives of countless patients with a variety of intestinal failure syndromes since the 1960s. Despite its life-saving properties, PN is not without complications, including PN-associated liver disease (PNALD). Recent studies have demonstrated that the composition of the lipid emulsion administered in combination with PN plays a pivotal role in the development of PNALD. Commonly used lipid emulsions are rich in soybean oil, which contain large quantities of pro-inflammatory omega-6 fatty acids and hepatotoxic phytosterols; these emulsions have been shown to cause liver injury in both in vitro and in vivo studies. Previous studies in our laboratory have demonstrated that an omega-3 FA rich fish oil-based lipid emulsion is protective against PNALD. Omega-3 FAs are metabolized to eicosapenaenoic acid (EPA) and docosahexaenoic acid (DHA), which increase the anti-inflammatory cytokines PGE3 and LTB5, and are suggested to contribute to the prevention of PNALD. A second mechanism which has recently been proposed to characterize the anti-inflammatory effects of omega-3 FAs involves the binding of a G-protein coupled receptor 120 (GPR120) with resultant inhibition of TNF-a and lipopolysaccharide-mediated inflammatory cascades. The purpose of this study is to determine whether the protective effect of fish oil-based lipid emulsions is mediated via the downstream metabolites of omega-3 FAs, or whether it results from the GPR120 receptor mediated pathway, or a combination of both mechanisms. To evaluate this further, two specific aims will be addressed. The first specific aim is to characterize the differences in insulin resistance, peripheral fat and liver inflammatory profiles, hepatosteatosis, and degree of liver injury within a PN fed murine model. To achieve this goal, GPR120 knockout (KO) mice and their wild-type (WT) littermates will be randomized to four groups. KO and WT control groups (KO control and WT control, respectively) will receive standard rodent chow. A third group will be comprised of KO mice receiving high-carbohydrate PN solution (HCD) with saline (KO HCD), and a fourth group will be comprised of WT mice receiving HCD (WT HCD). Serum inflammatory markers, adipose tissue and liver will be assessed among the four groups. The second specific aim is to determine if the GPR120 receptor is required for the reduction of tissue inflammation, hepatosteatosis and/or liver injury in a PN fed model. To achieve this goal, KO and WT mice will be randomized into six groups to receive saline, fish oil (FO) or soybean oil (SO) via tail injection concomitantly with HCD (KO control, KO HCD+FO, KO HCD+SO, WT control, WT HCD+FO, and WT HCD+SO). Markers of insulin resistance, peripheral fat inflammation and liver injury will be compared between groups.

描述（由申请人提供）：肠胃外营养（PN）已被认为是自1960年代以来挽救无数肠衰竭综合症患者的生命。尽管具有挽救生命的特性，但PN并非没有并发症，包括与PN相关的肝病（PNALD）。最近的研究表明，与PN结合使用的脂质乳液的组成在PNALD的发展中起关键作用。常用的脂质乳液富含大豆油，其中含有大量促炎的omega-6脂肪酸和肝毒性植物固醇。这些乳液已被证明在体外和体内研究中都会引起肝损伤。我们实验室中先前的研究表明，欧米茄-3 FA富含鱼油的脂质乳液对PNALD具有保护作用。 Omega-3 FAS代谢为eicosapenaenoic Acid（EPA）和二十二烯酸（DHA），它们增加了抗炎细胞因子PGE3和LTB5，并建议有助于预防PNALD。最近提出的第二种机制来表征Omega-3 Fas的抗炎作用，涉及G蛋白偶联受体120（GPR120）的结合，从而抑制TNF-A和脂多年营养不清的炎症炎症级联。这项研究的目的是确定鱼油基脂质乳液的保护作用是通过Omega-3 Fas的下游代谢产物介导的，还是是由GPR120受体介导的途径或两种机制组合引起的。为了进一步评估这一点，将解决两个具体目标。第一个具体目的是表征胰岛素抵抗，外周脂肪和肝脏炎症特征，肝炎和肝损伤程度的差异。为了实现这一目标，GPR120淘汰（KO）小鼠及其野生型（WT）同窝仔将被随机分为四组。 KO和WT对照组（KO对照组和WT控制）将获得标准的啮齿动物盘。第三组将由接受高碳水化合物PN溶液（HCD）（KO HCD）的KO小鼠组成，第四组将由接收HCD（WT HCD）的WT小鼠组成。血清炎症标记，脂肪组织和肝脏将在四组之间进行评估。第二个具体目的是确定在PN FED模型中减少组织炎症，肝炎和/或肝损伤是否需要GPR120受体。为了实现这一目标，KO和WT小鼠将被随机分为六组，以接受盐水，鱼油（FO）或大豆油（SO），通过尾部注射与HCD（KO Control，KO HCD+FO，KO HCD+SO，SO）同时接受尾注。 WT控制，WT HCD+FO和WT HCD+SO）。两组之间将比较胰岛素抵抗，外周脂肪炎症和肝损伤的标记。