Role of alcohol-induced ghrelin in modulating organ crosstalk to promote the development of fatty liver disease
酒精诱导的胃饥饿素在调节器官串扰促进脂肪肝发展中的作用
基本信息
- 批准号:10428677
- 负责人:
- 金额:$ 33.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-15 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdipocytesAdipose tissueAffectAgonistAlcohol consumptionAlcoholsAnimal ModelAttenuatedBenignBiologicalChronicCirrhosisComplexDevelopmentEnergy MetabolismEthanolExperimental Animal ModelFatty AcidsFatty LiverFibrosisFunctional disorderGastrointestinal HormonesGoalsHepaticHepatitisHepatocyteHormonesHumanImpairmentIn VitroInflammation MediatorsInsulinKnock-outLeadLipidsLipolysisLiverLiver diseasesMalignant NeoplasmsMediatingMetabolic DiseasesMetabolismNonesterified Fatty AcidsOrganPancreasPathogenesisPathologicPathologyPeptidesRattusReceptor Mediated Signal TransductionResistanceRoleSerumSignal TransductionStomachStructure of beta Cell of isletTechnologyTestingTherapeutic InterventionTherapeutic Usesadipokinesadiponectinalcohol abuse therapyalcohol effectalcohol exposureantagonistantimicrobial peptidebasecarbohydrate metabolismchronic alcohol ingestionfatty liver diseaseghrelinghrelin receptorglucagon-like peptide 1improvedinnovationinsightinsulin secretioninsulin sensitivityinterestlipid metabolismoxidationpeptide hormonepreventproblem drinkertargeted treatmentuptake
项目摘要
ABSTRACT:
Fatty liver (steatosis), characterized by an accumulation of lipids in hepatocytes, is one of the earliest pathological
changes in the progression of alcohol-associated fatty liver disease (AFLD). Pathophysiological mechanisms
involved during development of AFLD are complex and multifactorial, including gut, pancreas and adipose tissue
dysfunctions that reportedly affect liver pathology. Accumulating evidence has demonstrated that the crosstalk
between these organs are regulated by peptide hormones. Especially relevant to this proposal is the growing
interest in understanding the role of gut hormones in organ interactions and in the development of AFLD.
Among all the gastrointestinal hormones, the stomach-derived ghrelin is the one of the hormones that
significantly increases with chronic alcohol exposure in humans and experimental animal models. In our recent
studies, we demonstrated that an alcohol-induced increase in serum ghrelin levels impairs insulin secretion from
pancreatic β-cells. The consequent reduction in the circulating insulin levels promotes adipose lipolysis and
mobilization of fatty acids to the liver to ultimately contribute to hepatic steatosis. Concomitantly, chronic alcohol
treatment to rats increases serum levels of the gut hormone, glucagon-like peptide-1 (GLP-1) while decreasing
liver-expressed antimicrobial peptide-2 (LEAP-2) and adiponectin levels. Interestingly, these pathological
changes were not altered in ethanol-fed ghrelin receptor knockout (GHS-R KO) rats, which were also resistant
to steatosis development. Collectively, these results indicate a fundamental role of an alcohol-induced ghrelin
increase in affecting multiple organs, such as the gut and adipose to modulate GLP-1, insulin, adiponectin and
LEAP-2 activity/levels, to ultimately lead to the development of AFLD.
To study these effects, we present the following hypothesis: Alcohol-induced increase in serum ghrelin levels
directly (i) inhibits GLP-1 hormone-mediated energy metabolism in hepatocytes and (ii) modulates
adipose metabolism to increase adipose lipolysis and decrease adiponectin secretion, both of which
contribute to hepatic steatosis. Furthermore, ghrelin also enhances its effects by lowering the levels of
LEAP-2, recently discovered endogenous ghrelin antagonist peptide that reduces the ghrelin receptor
(GHS-R) mediated signal transduction.
We will utilize a variety of state-of-the art technologies and innovative biological concepts to explore our
hypothesis in three specific aims: 1) Characterize the role of ghrelin in modulating the gut-derived GLP-1
hormone-mediated gut-liver crosstalk during the development of AFLD; 2) Characterize the specific contribution
of ghrelin in modulating the adipose-liver axis in the development of ALFD; and 3) Examine the effect of alcohol-
induced ghrelin increase on LEAP-2 expression and characterize its role in modulating hepatic steatosis.
Successful completion of the proposed studies will aid mechanistic insights into understanding ghrelin’s role in
modulating the gut, adipose and liver axis to promote the development of alcoholic steatosis.
抽象的:
脂肪肝(脂肪变性),以肝细胞内脂质堆积为特征,是最早的病理性肝病之一。
酒精相关脂肪肝病(AFLD)病理生理机制的变化。
AFLD 的发生过程涉及复杂且多因素的因素,包括肠道、胰腺和脂肪组织
据报道影响肝脏病理学的功能障碍。越来越多的证据表明串扰。
这些器官之间的相互作用受到肽激素的调节,与这一提议特别相关的是日益增长的肽激素。
有兴趣了解肠道激素在器官相互作用和 AFLD 发展中的作用。
在所有胃肠道激素中,胃源性生长素释放肽是最能发挥作用的激素之一。
在人类和实验动物模型中,随着长期酒精暴露,该效应显着增加。
研究表明,酒精引起的血清生长素释放肽水平升高会损害胰岛素分泌
随之而来的循环胰岛素水平降低促进脂肪分解和
脂肪酸动员到肝脏,最终导致肝脏脂肪变性。
对大鼠进行治疗会增加肠道激素胰高血糖素样肽-1 (GLP-1) 的血清水平,同时降低
肝脏表达的抗菌肽-2 (LEAP-2) 和脂联素水平。
乙醇喂养的生长素释放肽受体敲除 (GHS-R KO) 大鼠的变化没有改变,这些大鼠也具有耐药性
总的来说,这些结果表明酒精诱导的生长素释放肽具有重要作用。
增加影响多个器官,例如肠道和脂肪,以调节 GLP-1、胰岛素、脂联素和
LEAP-2 活动/水平,最终导致 AFLD 的发展。
为了研究这些影响,我们提出以下假设: 酒精引起的血清生长素释放肽水平升高
直接 (i) 抑制肝细胞中 GLP-1 激素介导的能量代谢,以及 (ii) 调节
脂肪代谢增加脂肪分解并减少脂联素分泌,这两者
此外,胃饥饿素还通过降低
LEAP-2,最近发现的内源性生长素释放肽拮抗肽,可减少生长素释放肽受体
(GHS-R) 介导的信号转导。
我们将利用各种最先进的技术和创新的生物概念来探索我们的
三个具体目标的假设:1) 描述 ghrelin 在调节肠道来源的 GLP-1 中的作用
AFLD 发展过程中激素介导的肠-肝串扰 2) 描述具体贡献;
胃饥饿素在 ALFD 发展过程中调节脂肪肝轴的作用;以及 3) 检查酒精的影响
诱导 ghrelin 增加 LEAP-2 表达并表征其在调节肝脂肪变性中的作用。
成功完成拟议的研究将有助于深入了解 ghrelin 在
调节肠道、脂肪和肝轴,促进酒精性脂肪变性的发展。
项目成果
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Karuna Rasineni其他文献
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{{ truncateString('Karuna Rasineni', 18)}}的其他基金
Role of alcohol-induced ghrelin in modulating organ crosstalk to promote the development of fatty liver disease
酒精诱导的胃饥饿素在调节器官串扰促进脂肪肝发展中的作用
- 批准号:
10211947 - 财政年份:2021
- 资助金额:
$ 33.92万 - 项目类别:
Role of alcohol-induced ghrelin in modulating organ crosstalk to promote the development of fatty liver disease
酒精诱导的胃饥饿素在调节器官串扰促进脂肪肝发展中的作用
- 批准号:
10211947 - 财政年份:2021
- 资助金额:
$ 33.92万 - 项目类别:
Role of alcohol-induced ghrelin in modulating organ crosstalk to promote the development of fatty liver disease
酒精诱导的胃饥饿素在调节器官串扰促进脂肪肝发展中的作用
- 批准号:
10625844 - 财政年份:2021
- 资助金额:
$ 33.92万 - 项目类别:
Pancreas-Adipose-Liver Axis: Role of Ghrelin and Insulin in Alcoholic Fatty Liver
胰腺-脂肪-肝轴:生长素释放肽和胰岛素在酒精性脂肪肝中的作用
- 批准号:
9912676 - 财政年份:2016
- 资助金额:
$ 33.92万 - 项目类别:
Pancreas-Adipose-Liver Axis: Role of Ghrelin and Insulin in Alcoholic Fatty Liver
胰腺-脂肪-肝轴:生长素释放肽和胰岛素在酒精性脂肪肝中的作用
- 批准号:
9109961 - 财政年份:2016
- 资助金额:
$ 33.92万 - 项目类别:
Pancreas-Adipose-Liver Axis: Role of Ghrelin and Insulin in Alcoholic Fatty Liver
胰腺-脂肪-肝轴:生长素释放肽和胰岛素在酒精性脂肪肝中的作用
- 批准号:
9268735 - 财政年份:2016
- 资助金额:
$ 33.92万 - 项目类别:
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