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: 8255841
• 负责人: Sarah J Carlson
• 金额: $ 5.39万
• 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/8255841
• 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; Injury; 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; nutrition; prevent; prostaglandin E3; protective effect; 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. PUBLIC HEALTH RELEVANCE: In recent years, omega-3 fatty acids (FAs) have been shown to have a variety of health benefits in humans. With respect to the liver, previous studies have identified liver-protective and anti-inflammatory effects of omega-3 FAs when given to individuals who depend on intravenous nutrition for their daily caloric needs. The goal of this study is to characterize the molecular basis underlying the beneficial effects of omega-3 FAs and elucidate the mechanism in order to better diagnose, prevent, and treat tissue inflammation and liver disease.

描述（由申请人提供）：自20世纪60年代以来，肠外营养（PN）被认为挽救了无数患有各种肠衰竭综合征的患者的生命。尽管PN具有挽救生命的特性，但它并非没有并发症，包括PN相关肝病（PNALD）。最近的研究表明，与PN联合给药的脂肪乳剂的组成在PNALD的发生中起着关键作用。常用的脂肪乳剂富含大豆油，其中含有大量促炎性omega-6脂肪酸和肝毒性植物甾醇;这些乳剂在体外和体内研究中均显示可引起肝损伤。我们实验室以前的研究已经证明，富含omega-3 FA的鱼油脂肪乳剂对PNALD具有保护作用。Omega-3脂肪酸被代谢为二十碳五烯酸（EPA）和二十二碳六烯酸（DHA），增加抗炎细胞因子PGE 3和LTB 5，并被认为有助于预防PNALD。最近提出的表征ω-3FA的抗炎作用的第二种机制涉及G蛋白偶联受体120（GPR 120）的结合，从而抑制TNF-α和脂多糖介导的炎症级联反应。本研究的目的是确定鱼油脂肪乳剂的保护作用是通过omega-3 FA的下游代谢产物介导的，还是由GPR 120受体介导的途径产生的，还是两种机制的组合。为了进一步评估这一点，将讨论两个具体目标。第一个具体目的是表征PN喂养小鼠模型中胰岛素抵抗、外周脂肪和肝脏炎症特征、脂肪肝和肝损伤程度的差异。为了实现这一目标，将GPR 120敲除（KO）小鼠及其野生型（WT）同窝仔随机分为四组。KO和WT对照组（分别为KO对照和WT对照）将接受标准啮齿动物饲料。第三组由接受高碳水化合物PN溶液（HCD）和盐水（KO HCD）的KO小鼠组成，第四组由接受HCD（WT HCD）的WT小鼠组成。将在四个组中评估血清炎症标志物、脂肪组织和肝脏。第二个具体目的是确定GPR 120受体是否是减少PN喂养模型中组织炎症、脂肪肝和/或肝损伤所必需的。为了实现这一目标，KO和WT小鼠将随机分为6组，通过尾部注射接受生理盐水、鱼油（FO）或大豆油（SO），同时接受HCD（KO对照、KO HCD+FO、KO HCD+SO、WT对照、WT HCD+FO和WT HCD+SO）。将比较两组之间的胰岛素抵抗、外周脂肪炎症和肝损伤标志物。 公共卫生相关性：近年来，omega-3脂肪酸（FAs）已被证明对人类具有多种健康益处。关于肝脏，以前的研究已经确定了omega-3脂肪酸在给予依赖静脉营养来满足日常热量需求的个体时的肝脏保护和抗炎作用。本研究的目的是表征omega-3脂肪酸有益作用的分子基础，并阐明其机制，以便更好地诊断，预防和治疗组织炎症和肝脏疾病。