Nutrition and Nonalcoholic Fatty Liver Disease

营养与非酒精性脂肪肝

基本信息

批准号：
8213673
负责人：
Zhiping Li
金额：
$ 34.16万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-18 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8213673
关键词：
Address Adoptive Transfer Animal Model Anti-Inflammatory Agents Anti-inflammatory Bacteria Biochemical Cell Count Cell Survival Cells Cellular Structures Characteristics Chronic Cirrhosis Clinical Data Diet Diet Habits Dietary Component Dietary Factors Dietary Fatty Acid Elements Equilibrium Fatty Acids Fatty Liver Fatty acid glycerol esters Future Genes Glucose Intolerance Goals Health Hepatic Hepatocyte Histology Home environment Homeostasis Homing Hyperlipidemia Hypertension Immune system Incidence Inflammation Inflammatory Inflammatory Response Insulin Resistance Intestines Lead Liver Liver diseases Lymphocyte Mediating Mediator of activation protein Metabolic syndrome Modeling Molecular Morbidity - disease rate Mus Nutritional Obesity Pathogenesis Pathology Pathway interactions Phosphotransferases Population Probiotics Production Regulation Relative (related person)Research Rodent Screening procedure Severities Signal Transduction System T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues Tumor Necrosis Factor-alpha United States National Institutes of Health Work base carbohydrate metabolism cytokine feeding gut microflora improved in vivo inhibitor/antagonist insulin signaling mortality non-alcoholic fatty liver nonalcoholic steatohepatitis novel nutrition prevent receptor salicylate trend

项目摘要

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is increasing rapidly among the US population, and has become major health concerns. NAFLD is often associated with elements of the metabolic syndrome, a clinical constellation of obesity, hypertension, insulin resistance, glucose intolerance and hyperlipidemia. The spectrum of NAFLD extends from simple hepatic steatosis through nonalcoholic steatohepatitis (NASH) to cirrhosis. Liver-related morbidity and mortality correlate with the histological severity of NAFLD. Among various factors that contribute to the rising incidence of NAFLD, dietary factors are known to promote obesity and fatty liver disease. Our long-term objectives are to understand the underlying biochemical and molecular mechanisms which dietary factors contribute to NAFLD pathogenesis and to develop strategies that prevent and treat fatty liver disease. Our preliminary studies show that some of the same dietary factors that promote obesity and fatty liver also influence hepatic NKT cells, components of the innate immune system that balance the local production of pro-inflammatory and anti-inflammatory cytokines. Pro-inflammatory cytokines are known to induce insulin resistance and fatty liver disease. Therefore, alterations in NKT cell populations might cause the relative over-production of Th1 cytokines and tissue-specific insulin resistance. This observation suggests a novel mechanism by which dietary components themselves might modulate inflammatory responses that, in turn, regulate insulin resistance and lead to fatty liver. We plan to evaluate the HYPOTHESIS that certain dietary fatty acids alter liver NKT cell populations, thereby influencing the function of the hepatic innate immune system and causing a local, chronic inflammatory state that ultimately leads to local and systemic insulin resistance and fatty liver disease. Three specific aims will be addressed: AIM 1 is to determine the dietary basis for alterations in NKT cell populations and firmly establish the causal relation between hepatic NKT cell depletion and steatosis, AIM 2 is to identify the mechanisms of diet-induced NKT cell depletion, and AIM 3 is to identify the mechanisms that NKT cells regulate the pathogenesis of insulin resistance and steatosis. Mice will be fed certain high fat diets to induce obesity and NAFLD. Hepatic lymphocyte population, inflammatory cytokine expressions and liver histology will be evaluated. Confirmation of this hypothesis has potential implications to develop a more accurate animal model of NAFLD and define molecular characteristics (the NIH Action Plan for Liver Disease Research, Chapter 7, Matrix Cell A3). Results from these proposed studies will help to elucidate the pathogenesis of NAFLD, and may have profound therapeutic implications to identify targets for therapy that might be used in rapid- throughput screening systems (the NIH Action Plan for Liver Disease Research, Chapter 7, Matrix Cell B3).

描述（由申请人提供）：非酒精性脂肪肝病（NAFLD）在美国人口中正在迅速增加，并且已成为主要的健康问题。 NAFLD通常与代谢综合征的元素，肥胖，高血压，胰岛素抵抗，葡萄糖不耐症和高脂血症的临床星座有关。 NAFLD的光谱从简单的肝脂肪变性到非酒精性脂肪性肝炎（NASH）到肝硬化。与肝有关的发病率和死亡率与NAFLD的组织学严重程度相关。在导致NAFLD发病率上升的各种因素中，饮食因素已知可以促进肥胖和脂肪肝病。我们的长期目标是了解饮食因素有助于NAFLD发病机理的基本生化和分子机制，并制定预防和治疗脂肪肝病的策略。我们的初步研究表明，促进肥胖和脂肪肝的一些饮食因素也会影响肝NKT细胞，肝NKT细胞是先天免疫系统的成分，这些组成部分平衡了局部产生的促炎和抗炎细胞因子的局部产生。促炎性细胞因子已知会诱导胰岛素抵抗和脂肪肝病。因此，NKT细胞群体的改变可能导致Th1细胞因子和组织特异性胰岛素抵抗的相对过量产生。该观察结果表明了一种新的机制，饮食成分本身可能会调节炎症反应，从而调节胰岛素抵抗并导致脂肪肝。我们计划评估某些饮食脂肪酸改变肝脏NKT细胞群体的假设，从而影响肝的先天免疫系统的功能，并导致局部慢性炎症状态，最终导致局部和系统性的胰岛素抵抗和脂肪肝疾病。将解决三个具体目的：目标1是确定NKT细胞群体改变的饮食基础，并牢固地建立肝NKT细胞耗竭和脂肪变性之间的因果关系，目的2是确定饮食诱导的NKT细胞耗竭的机制，目标3是确定NKT细胞的机制。小鼠将得到某些高脂肪饮食的喂养，以诱导肥胖和NAFLD。将评估肝淋巴细胞种群，炎性细胞因子表达和肝组织学。对该假设的确认具有潜在的意义，以开发更准确的NAFLD动物模型并定义分子特征（肝病研究的NIH行动计划，第7章，基质细胞A3）。这些提出的研究的结果将有助于阐明NAFLD的发病机理，并可能具有深远的治疗意义，以识别可能用于快速吞吐量筛查系统的治疗靶标（NIH肝病研究计划，第7章，矩阵细胞B3）。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of gut microbiota in liver diseases.

DOI：
10.1111/j.1872-034x.2012.01088.x
发表时间：
2013-02
期刊：
Hepatology research : the official journal of the Japan Society of Hepatology
影响因子：
0
作者：
Miyake Y;Yamamoto K
通讯作者：
Yamamoto K

Randomized, controlled pilot study comparing large-volume paracentesis using wall suction and traditional glass vacuum bottle methods.

比较使用壁抽吸和传统玻璃真空瓶方法进行大容量腹腔穿刺术的随机对照试点研究。

DOI：
10.1177/1756283x14532704
发表时间：
2014
期刊：
Therapeutic advances in gastroenterology
影响因子：
4.2
作者：
Konerman,MonicaA;Price,Jennifer;Torres,Dawn;Li,Zhiping
通讯作者：
Li,Zhiping

Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression.

DOI：
10.1371/journal.pone.0018909
发表时间：
2011-04-19
期刊：
PloS one
影响因子：
3.7
作者：
Zhao L;Tang Y;You Z;Wang Q;Liang S;Han X;Qiu D;Wei J;Liu Y;Shen L;Chen X;Peng Y;Li Z;Ma X
通讯作者：
Ma X

String-like micellar nanoparticles formed by complexation of PEG-b-PPA and plasmid DNA and their transfection efficiency.

DOI：
10.1007/s11095-011-0436-3
发表时间：
2011-06
期刊：
Pharmaceutical research
影响因子：
3.7
作者：
Jiang X;Leong D;Ren Y;Li Z;Torbenson MS;Mao HQ
通讯作者：
Mao HQ

Endoscopic visceral fat removal as therapy for obesity and metabolic syndrome: a sham-controlled pilot study (with video).

DOI：
10.1016/j.gie.2011.07.006
发表时间：
2011-09
期刊：
Gastrointestinal endoscopy
影响因子：
7.7
作者：
Lang Xia;J. Hua;X. Dray;M. Khashab;S. Liang;Yongsik Kim;C. Jimeno-Ayllón;A. Kalloo;Zhiping Li
通讯作者：
Lang Xia;J. Hua;X. Dray;M. Khashab;S. Liang;Yongsik Kim;C. Jimeno-Ayllón;A. Kalloo;Zhiping Li