Hepatic insulin resistance integrates T2D and NAFLD
肝脏胰岛素抵抗整合了 T2D 和 NAFLD
基本信息
- 批准号:10792348
- 负责人:
- 金额:$ 15.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationActivinsAdipose tissueAdultAlbuminsAmendmentAnimalsAttenuatedAwardBenignBeveragesCholesterolChronicClinicalConsumptionDataDiabetes MellitusDietDisease ProgressionDyslipidemiasEconomic BurdenEpidemicEsterificationFOXO1A geneFamilyFatty AcidsFatty LiverFatty acid glycerol estersFeedbackFibrosisFollistatinFoodFructoseGDF8 geneGene ExpressionGeneticGenetic TranscriptionGlucoseGlucose IntoleranceGlycerolHealthHepaticHepatocyteHigh Fat DietHumanHyperinsulinismImpairmentInflammationInflammatoryInsulinInsulin ReceptorInsulin ResistanceKetohexokinaseLabelLegLifeLigandsLinkLipolysisLiverLiver FibrosisMediatingMetabolicMetabolic DiseasesMetabolismModelingMusNon-Insulin-Dependent Diabetes MellitusNutrientObesityPIK3CG genePathway interactionsPatientsPeripheralPersonsPhosphorylationPhosphotransferasesResistanceRisk FactorsSignal TransductionSiteSourceSucroseTNF geneTestingThinnessTissuesTranscriptional RegulationTransforming Growth Factor betaTransgenic MiceTriglyceridesWorkalpha-glycerophosphoric acidblood glucose regulationexperimental studyfeedingfibroblast growth factor 21glucose outputglucose productioninsulin receptor substrate 1 proteininsulin secretioninsulin signalinglipid biosynthesisliver inflammationliver metabolismmetabolomicsmouse geneticsnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelrecruitsaturated fatsugarwestern diet
项目摘要
This proposal investigates mechanisms that combine T2D (type 2 diabetes) with NAFLD (non-alcoholic fatty
liver disease), which progress during chronic hepatic insulin resistance to life-threatening NASH (non-alcoholic
steatohepatitis). Several studies argue that selective hepatic insulin resistance is required to integrate T2D with
NAFLD/NASH. Regardless, we posit that complete hepatic insulin resistance exacerbates NAFLD/NASH and
T2D in mice fed the western GAN diet—which models common sugar-sweetened food and beverages
associated with T2D and NAFLD/NASH in patients. We model complete hepatic insulin resistance with ‘LDKO’
mice that lack hepatic Irs1 (insulin receptor substrate 1) and Irs2, which activates FoxO1 mediated
transcription to induce hepatic Fst (follistatin) expression and secretion. Circulating hepatic Fst causes WAT
(white adipose tissue) insulin resistance and uncontrolled lipolysis. Circulating FST in human NAFLD patients
correlates with insulin resistance in leg fat to release fatty acids from this benign storage site. Our proposal
investigates whether hepatic FoxO1 and Fst promote the progression of NAFLD to NASH during hepatic
insulin resistance. We use mouse genetics to determine whether inactivation of FoxO1 or Fst in LDKO mice
fed the GAN diet can attenuate both NAFLD/NASH trajectory and liver inflammatory gene expression to
identify pathways promoting NAFLD and its progression to NASH during hepatic insulin resistance. We test
this hypothesis by inactivating TNFα in LDKO mice fed the GAN diet. A simpler high-fructose diet (HFruD60%) is
used to investigate whether FoxO1 and Fst promote NAFLD/NASH from hepatic fructose metabolism. Re-
esterification of circulating fatty acids with hepatic Gro3P (glycerol-3-phosphate)—a fructose metabolite—is a
major source of hepatic triacylglycerol in NAFLD patients. To understand whether fructose promotes
NAFLD/NASH by re-esterification of circulating fatty acid during complete hepatic insulin resistance, we can
investigate LDKO mice fed the HFruD60% without or after deletion of hepatic FoxO1 or Fst—or Khk
(Ketohexokinase) that is essential for hepatic metabolism of fructose. Feeding mice [13C]fructose enables LC-
MS to determine the incorporation of fructose metabolites into the glycerol or fatty acid moieties of liver or
circulating triacylglycerol. In humans and mice, NAFLD might arise from ‘selective insulin resistance’—owing to
uncontrolled hepatic glucose output in conjunction with some insulin-stimulated lipogenesis; however, we posit
that selective hepatic insulin resistance might have the opposite effect and attenuate NAFLD/NASH owing to
inhibition of FoxO1 and Fst. Since chronic nutrient excess can suppress hepatic Irs2, we investigate GAN diet-
induced NAFLD/NASH and T2D in mice lacking hepatic Irs2 (LKO2 mice) or Irs1 (LKO1 mice), as well as our
novel transgenic mice expressing nutrient-insensitive Irs2tg in hepatocytes. Completion of our proposal can
impact human health by identifying systemic and hepatic metabolic regulatory mechanisms by which hepatic
insulin resistance integrates T2D with NAFLD/NASH.
该提案研究了联合收割机T2 D(2型糖尿病)与NAFLD(非酒精性脂肪肝)相结合的机制。
肝脏疾病),其在慢性肝脏胰岛素抵抗期间进展为危及生命的NASH(非酒精性
脂肪性肝炎)。几项研究认为,选择性肝胰岛素抵抗是整合T2 D与
NAFLD/NASH。无论如何,我们认为完全的肝脏胰岛素抵抗会加重NAFLD/NASH,
喂食西方GAN饮食的小鼠中的T2 D-其模拟常见的含糖食物和饮料
与T2 D和NAFLD/NASH相关。我们用“LDKO”模拟完全肝胰岛素抵抗
缺乏肝脏Irs 1(胰岛素受体底物1)和Irs 2(激活FoxO 1介导的
转录以诱导肝Fst(卵泡抑素)表达和分泌。循环肝Fst导致WAT
(白色脂肪组织)胰岛素抵抗和不受控制的脂解。人类NAFLD患者的循环FST
与腿部脂肪中的胰岛素抵抗相关,以从这个良性储存部位释放脂肪酸。我们的建议
研究肝脏FoxO 1和Fst是否促进肝脏中NAFLD向NASH的进展,
胰岛素抵抗我们使用小鼠遗传学来确定LDKO小鼠中FoxO 1或Fst的失活是否
喂食GAN饮食可以减弱NAFLD/NASH轨迹和肝脏炎症基因表达,
确定在肝胰岛素抵抗期间促进NAFLD及其进展为NASH的途径。我们测试
通过灭活喂食GAN饮食的LDKO小鼠中的TNFα证实了这一假设。一个简单的高果糖饮食(HFruD 60%)是
用于研究FoxO 1和Fst是否促进来自肝脏果糖代谢的NAFLD/NASH。再-
循环脂肪酸与肝Gro 3 P(甘油-3-磷酸)-果糖代谢物-的酯化作用是一种
是NAFLD患者肝脏三酰甘油的主要来源。为了了解果糖是否能促进
通过在完全肝胰岛素抵抗期间循环脂肪酸的再酯化,我们可以
研究喂食HFruD 60%而不含或缺失肝脏FoxO 1或Fst-或Khk后的LDKO小鼠
(己酮糖激酶),其对于果糖的肝代谢是必需的。喂食小鼠[13 C]果糖可使LC-
MS测定果糖代谢产物掺入肝脏的甘油或脂肪酸部分,或
循环甘油三酯。在人类和小鼠中,NAFLD可能是由“选择性胰岛素抵抗”引起的,
不受控制的肝葡萄糖输出与一些胰岛素刺激的脂肪生成有关;然而,我们认为,
由于选择性肝脏胰岛素抵抗可能会产生相反的作用并减轻NAFLD/NASH,
抑制FoxO 1和Fst.由于慢性营养过剩可以抑制肝脏Irs 2,我们研究了GAN饮食-
在缺乏肝脏Irs 2(LKO 2小鼠)或Irs 1(LKO 1小鼠)的小鼠中诱导NAFLD/NASH和T2 D,以及我们的
在肝细胞中表达营养不敏感的Irs 2 tg的新型转基因小鼠。完成我们的提案可以
通过识别系统和肝脏代谢调节机制来影响人类健康,
胰岛素抵抗整合了T2 D与NAFLD/NASH。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Morris F. White其他文献
The IRS-Pathway Operates Distinctively From the Stat-Pathway in Hematopoietic Cells and Transduces Common and Distinct Signals During Engagement of the Insulin or Interferon-α Receptors
- DOI:
10.1182/blood.v90.7.2574 - 发表时间:
1997-10-01 - 期刊:
- 影响因子:
- 作者:
Shahab Uddin;Eleanor N. Fish;Dorie Sher;Concetta Gardziola;Oscar R. Colamonici;Merrill Kellum;Paula M. Pitha;Morris F. White;Leonidas C. Platanias - 通讯作者:
Leonidas C. Platanias
Early biochemical events in insulin-stimulated fluid phase endocytosis
胰岛素刺激的液相内吞作用的早期生化事件
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:0
- 作者:
D. Pitterle;R. Sperling;M. G. Myers;Morris F. White;P. J. Blackshear - 通讯作者:
P. J. Blackshear
Extreme makeover of pancreatic α-cells
胰腺α细胞的极端改造
- DOI:
10.1038/4641132a - 发表时间:
2010-04-21 - 期刊:
- 影响因子:48.500
- 作者:
Kenneth S. Zaret;Morris F. White - 通讯作者:
Morris F. White
Stimulation of pancreatic beta-cell proliferation by growth hormone is glucose-dependent: signal transduction via janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) with no crosstalk to insulin receptor substrate-mediated mitogenic signalling.
生长激素对胰腺 β 细胞增殖的刺激是葡萄糖依赖性的:通过 janus 激酶 2 (JAK2)/信号转导器和转录激活剂 5 (STAT5) 进行信号转导,与胰岛素受体底物介导的有丝分裂信号传导没有串扰。
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:4.1
- 作者:
S. P. Cousin;S. Hügl;M. G. Myers;Morris F. White;Anne Reifel;Christopher J. Rhodes - 通讯作者:
Christopher J. Rhodes
Insulin receptor substrate proteins and diabetes
- DOI:
10.1007/bf02980074 - 发表时间:
2004-04-01 - 期刊:
- 影响因子:7.500
- 作者:
Yong Hee Lee;Morris F. White - 通讯作者:
Morris F. White
Morris F. White的其他文献
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{{ truncateString('Morris F. White', 18)}}的其他基金
Regulation of hippocampal function by central and peripheral IRS signaling
通过中枢和外周 IRS 信号调节海马功能
- 批准号:
10343848 - 财政年份:2020
- 资助金额:
$ 15.05万 - 项目类别:
Regulation of hippocampal function by central and peripheral IRS signaling
通过中枢和外周 IRS 信号调节海马功能
- 批准号:
10162475 - 财政年份:2020
- 资助金额:
$ 15.05万 - 项目类别:
Regulation of hippocampal function by central and peripheral IRS signaling
通过中枢和外周 IRS 信号调节海马功能
- 批准号:
10548150 - 财政年份:2020
- 资助金额:
$ 15.05万 - 项目类别:
Hepatic insulin resistance and metabolic disease
肝脏胰岛素抵抗与代谢疾病
- 批准号:
8482791 - 财政年份:2013
- 资助金额:
$ 15.05万 - 项目类别:
Metabolic Crosstalk During Hepatic Insulin Resistance
肝脏胰岛素抵抗期间的代谢串扰
- 批准号:
9749986 - 财政年份:2013
- 资助金额:
$ 15.05万 - 项目类别:
Hepatic insulin resistance and metabolic disease
肝脏胰岛素抵抗与代谢疾病
- 批准号:
8637073 - 财政年份:2013
- 资助金额:
$ 15.05万 - 项目类别:
Hepatic insulin resistance and metabolic disease
肝脏胰岛素抵抗与代谢疾病
- 批准号:
8829241 - 财政年份:2013
- 资助金额:
$ 15.05万 - 项目类别:
Metabolic Crosstalk During Hepatic Insulin Resistance
肝脏胰岛素抵抗期间的代谢串扰
- 批准号:
9982302 - 财政年份:2013
- 资助金额:
$ 15.05万 - 项目类别:
Gordon Conference: Second Messengers and Phosphorylation
戈登会议:第二信使和磷酸化
- 批准号:
6535541 - 财政年份:2002
- 资助金额:
$ 15.05万 - 项目类别:
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