Effects of Hepatic Acetyl-CoA Carboxylase Inhibition on NAFLD and Hepatic Insulin Resistance
Effects of Hepatic Acetyl-CoA Carboxylase Inhibition on NAFLD and Hepatic Insulin Resistance
批准号:
10217114
负责人:
GERALD I SHULMAN
金额:
$72.94万
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
项目状态:
已结题
起止时间:
2017-09-15 至 2023-07-31
关键词:
Acetyl-CoA CarboxylaseAdipocytesAdipose tissueAffectAlcoholic Liver CirrhosisAnimal ModelAntisense OligonucleotidesChronicCirrhosisCitrate (si)-SynthaseDataDevelopmentDiabetes MellitusDiseaseDouble-Blind MethodEnergy MetabolismEnzymesFatty LiverFatty acid glycerol estersGeneral PopulationGluconeogenesisGlucoseGlucose ClampGlycerolGrantHepaticHepatitis CHumanHypertriglyceridemiaIndirect CalorimetryInsulinInsulin ResistanceLipidsLiverLiver MitochondriaMagnetic Resonance SpectroscopyMediatingMethodsModelingMuscleNon-Insulin-Dependent Diabetes MellitusNon-Rodent ModelPalmitatesPhasePhase II Clinical TrialsPlacebosPredisposing FactorPrimary carcinoma of the liver cellsPyruvate CarboxylaseRandomizedRattusSkeletal MuscleTestingTracerTranslatingTriglyceridesbeta-Hydroxybutyratefatty acid oxidationglobal healthglucose metabolismglucose productionimprovedin vivoinhibitor/antagonistinsightinsulin sensitivityketogenesislipid biosynthesislipid metabolismliver transplantationnew therapeutic targetnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnondrug therapynovelnovel therapeuticsoxidationrespiratorysmall molecule inhibitor
中文摘要
据估计,非酒精性脂肪性肝病(NAFLD)影响多达三分之一的普通人群,
NAFLD、肝脏胰岛素抵抗与2型糖尿病(T2D)密切相关。NAFLD是
也是发展为非酒精性脂肪性肝炎(NASH)、肝硬变和
预计NAFLD诱导的NASH很快将超过丙型肝炎和
酒精性肝硬变是美国肝移植最常见的适应症。因此,有一种
对有效降低肝脏脂肪变性和肝脏胰岛素抵抗的新药的巨大需求尚未得到满足。
在这项资助中,我们将研究一种新的肝靶向小分子乙酰辅酶A抑制剂的慢性效应。
羧化酶对非酒精性脂肪肝患者肝甘油三酯含量及糖脂代谢的影响
在一项随机、双盲、安慰剂对照的平行分组研究中。具体来说,我们将检查
一种新型肝靶向小分子乙酰辅酶A羧化酶抑制剂的慢性(21天)效应:1)
用~1H磁共振波谱(MRS)测定肝脏甘油三酯含量2)肝脏、骨骼
高胰岛素-正常血糖钳夹联合应用评价肌肉和脂肪细胞的胰岛素敏感性
[6,6-2H2]葡萄糖、[2H5]甘油和[13C16]棕榈酸酯周转,3)肝线粒体氧化速率
通过活体~(13)C磁共振波谱直接评估,4)评估肝酮体生成率
通过[13C4]β-羟丁酸周转,5)肝新生脂肪生成和糖异生
2H2O,6)肝丙酮酸羧化酶通量(VPC)/柠檬酸合成酶通量(VCS)的相对通量
新的位置异构体核磁共振示踪分析(PINTA)方法和全身能量消耗,
间接量热法测定VO2、VCO2、呼吸商。我们假设慢性抑制
乙酰辅酶A羧化酶将导致肝脏线粒体脂肪增加,从而减轻肝脏脂肪变性
氧化,降低DNL。我们还预计,这种肝脏脂肪变性的减少将与
肝脏胰岛素敏感性的改善,反映为肝脏葡萄糖产生的抑制增加
一种高胰岛素-正常血糖钳夹。这些研究的结果将提供重要的新的概念证明。
肝靶向乙酰辅酶A羧基酶抑制作为治疗NAFLD和T2D以及
肝靶向乙酰辅酶A羧基酶抑制机制的新认识
减少肝脏脂肪变性,降低肝脏胰岛素抵抗,改变肝脏线粒体脂肪氧化。
好了!
英文摘要
Non alcoholic fatty liver disease (NAFLD) is estimated to affect up to one third of the general population and
there is a strong relationship between NAFLD, hepatic insulin resistance and type 2 diabetes (T2D). NAFLD is
also a key predisposing factor for the development of non-alcoholic steatohepatitis (NASH), cirrhosis and
hepatocellular carcinoma and it is anticipated that NAFLD-induced NASH will soon surpass hepatitis C and
alcoholic cirrhosis as the most common indication for liver transplantation in the USA. Therefore there is a
great unmet need for new drugs that are effective at reducing hepatic steatosis and hepatic insulin resistance.
In this grant we will examine the chronic effects of a novel liver-targeted small molecule inhibitor of acetyl-CoA
carboxylase on hepatic triglyceride content as well as hepatic glucose and lipid metabolism in NAFLD subjects
in a randomized double-blinded placebo-controlled parallel group study. Specifically we will examine the
chronic (21 days) effects of a novel liver-targeted small molecule inhibitor of acetyl-CoA carboxylase on: 1)
Hepatic triglyceride content assessed by 1H magnetic resonance spectroscopy (MRS), 2) Hepatic, skeletal
muscle and adipocyte insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp in conjunction with
[6,6-2H2]glucose, [2H5]glycerol, and [13C16]palmitate turnover, 3) Rates of hepatic mitochondrial oxidation
directly assessed by in vivo 13C magnetic resonance spectroscopy, 4) Rates of hepatic ketogenesis assessed
by [13C4]β-hydroxybutyrate turnover, 5) Hepatic de novo lipogenesis (DNL) and gluconeogenesis assessed by
2H2O, 6) Relative flux rates of hepatic pyruvate carboxylase flux (VPC)/citrate synthase flux (VCS) assessed by a
novel Positional Isotopomer NMR Tracer Analysis (PINTA) method and 7) Whole body energy expenditure,
VO2, VCO2, respiratory quotient assessed by indirect calorimetry. We hypothesize that chronic inhibition of
acetyl-CoA carboxylase will result in decreased hepatic steatosis due to increased hepatic mitochondrial fat
oxidation and decreased DNL. We also anticipate that this reduction in hepatic steatosis will be associated with
improved hepatic insulin sensitivity as reflected by increased suppression of hepatic glucose production during
a hyperinsulinemic-euglycemic clamp. The results of these studies will provide important new proof of concept
data in support of liver-targeted acetyl CoA carboxylase inhibition as a therapy for NAFLD and T2D as well as
fundamental new insights into the mechanisms by which liver-targeted acetyl CoA carboxylase inhibition
reduces hepatic steatosis, decreases hepatic insulin resistance and alters hepatic mitochondrial fat oxidation.
!
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
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Effects of Hepatic Acetyl-CoA Carboxylase Inhibition on NAFLD and Hepatic Insulin Resistance
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国内基金
海外基金
支链氨基酸代谢紊乱调控“Adipocytes - Macrophages Crosstalk”诱发2型糖尿病脂肪组织功能和结构障碍的作用及机制
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依托单位: