A Role of Hypothalamic Dysfunction in Alcoholic Liver Disease
下丘脑功能障碍在酒精性肝病中的作用
基本信息
- 批准号:9530801
- 负责人:
- 金额:$ 1.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-24 至 2018-01-31
- 项目状态:已结题
- 来源:
- 关键词:Adipose tissueAlcohol consumptionAlcoholic Liver DiseasesAlcoholismAlcoholsAmino AcidsAnimalsAutonomic nervous systemBrainCannulasCarbohydratesChemicalsChronicClosure by clampCoculture TechniquesComplementConsciousDataDefectDilution TechniquesEndoplasmic ReticulumEuglycemic ClampingGeneticGlucoseHepaticHepatocyteHomeostasisHormonesHypothalamic dysfunctionHypothalamic structureImpairmentIn VitroInflammationInflammatoryInfusion proceduresInstructionInsulinInsulin ReceptorInsulin ResistanceKupffer CellsLipid ALipidsLipolysisLiverLiver FibrosisLiver diseasesMetabolicMetabolismModelingMusNatural ImmunityNeuronsNeurosecretory SystemsNeurotransmittersOrganOxidative StressPathogenesisPathway interactionsPeripheralPharmacologyPlayPredispositionPreventionProtein Tyrosine PhosphataseRattusRegulationRegulatory PathwayRisk FactorsRoleSignal PathwaySignal TransductionTestingTracerTransgenic ModelUp-RegulationVery low density lipoproteinalcohol effectalcohol researchalcohol testingbasebinge drinkingcarbohydrate metabolismcell typechronic alcohol ingestionendoplasmic reticulum stressfeedingglucose metabolismglucose productionglucose toleranceimpaired glucose tolerancein vivoinflammatory markerinflammatory milieuinsulin signalingintrahepaticlipid metabolismliver metabolismmouse modelneurotoxicnon-alcoholic fatty livernovelpreventprotein expressionrestorationsmall molecule inhibitorstellate cell
项目摘要
Insulin resistance is an important risk factor for alcoholic liver disease (ALD). Vice versa, heavy alcohol
consumption induces insulin resistance that is associated with progression of hepatic fibrosis in
non-alcoholic fatty liver disease (NAFLD). Insulin is the key hormone that regulates lipid and glucose
metabolism; it is also an important regulator of inflammation. Thus, hepatic insulin action is likely a key
player in the pathogenesis of ALD, yet the mechanisms through which impaired insulin action predisposes
to ALD remain poorly understood. We and others have previously demonstrated that insulin signaling within
the mediobasal hypothalamus (MBH) controls hepatic glucose production (hGP), very low density
lipoprotein (VLDL) secretion, white adipose tissue (WAT) lipolysis and innate immunity through the
autonomic nervous system. Based on our pilot data that demonstrate that in a rat model for binge drinking,
i.e. short term alcohol consumption impairs glucose tolerance and induces insulin resistance that is due to
impaired hepatic insulin action. Binge drinking markedly impairs hypothalamic insulin action, defined as the
ability of hypothalamic insulin to suppress hGP and adipose tissue lipolysis. Thus, the major hypothesis
proposed in this proposal is that some of the metabolic and innate immunity defects induced by alcohol are
caused through brain effects disrupting autonomic control of both metabolism and innate immunity. In
support ofthis novel paradigm we find that a central cause ofthe impaired hypothalamic insulin action is
decreased insulin signaling in the hypothalamus likely due to increased inflammation, ER stress and
expression of protein tyrosine phosphatase l b (PTPIb), a negative regulator of insulin signaling. Here we
propose to delineate the mechanisms through which chronic alcohol consumption impairs insulin action,
disrupts hepatic carbohydrate, amino acid and lipid metabolism and generates a pro-inflammatory
environment within the liver that predisposes to ALD.
胰岛素抵抗是酒精性肝病(ALD)的重要危险因素。反之亦然,重度酒精
消费会诱导胰岛素抵抗,这与肝纤维化的进展有关
非酒精性脂肪肝(NAFLD)。胰岛素是调节脂质和葡萄糖的关键激素
代谢;它也是炎症的重要调节剂。因此,肝脏胰岛素作用可能是关键
ALD 的发病机制中发挥着重要作用,但胰岛素作用受损导致的机制
对 ALD 的了解仍知之甚少。我们和其他人之前已经证明,胰岛素信号传导
下丘脑内侧基底节 (MBH) 控制肝葡萄糖生成 (hGP),密度极低
脂蛋白(VLDL)分泌、白色脂肪组织(WAT)脂肪分解和先天免疫通过
自主神经系统。根据我们的试点数据表明,在酗酒的大鼠模型中,
即短期饮酒会损害葡萄糖耐量并诱发胰岛素抵抗,这是由于
肝脏胰岛素作用受损。酗酒会明显损害下丘脑胰岛素的作用,定义为
下丘脑胰岛素抑制 hGP 和脂肪组织脂解的能力。因此,主要假设
该提案提出的是,酒精引起的一些代谢和先天免疫缺陷是
由大脑影响破坏新陈代谢和先天免疫的自主控制引起。在
为了支持这一新范式,我们发现下丘脑胰岛素作用受损的一个主要原因是
下丘脑的胰岛素信号减弱可能是由于炎症增加、内质网应激和
蛋白酪氨酸磷酸酶 l b (PTPIb) 的表达,PTPIb 是胰岛素信号传导的负调节因子。在这里我们
提议描述长期饮酒损害胰岛素作用的机制,
破坏肝脏碳水化合物、氨基酸和脂质代谢并产生促炎物质
肝脏内的环境容易导致 ALD。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway.
- DOI:10.1016/j.molmet.2023.101723
- 发表时间:2023-07
- 期刊:
- 影响因子:8.1
- 作者:Metz, Matthaeus;O'Hare, James;Cheng, Bob;Puchowicz, Michelle;Buettner, Christoph;Scherer, Thomas
- 通讯作者:Scherer, Thomas
How does leptin restore euglycemia in insulin-deficient diabetes?
- DOI:10.1172/jci91880
- 发表时间:2017-02-01
- 期刊:
- 影响因子:15.9
- 作者:Oberlin, Douglas;Buettner, Christoph
- 通讯作者:Buettner, Christoph
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CHRISTOPH BUETTNER其他文献
CHRISTOPH BUETTNER的其他文献
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Neural mechanisms for VGF regulation of energy balance
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A Role of Hypothalamic Dysfunction in Alcoholic Liver Disease
下丘脑功能障碍在酒精性肝病中的作用
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8859014 - 财政年份:2014
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A Role of Hypothalamic Dysfunction in Alcoholic Liver Disease
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