Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease

StephenW

PNAS                           
Proceedings of the National Academy of Sciences of the United States of                  America
        
Cellular mechanism of insulin         
resistance in nonalcoholic fatty liver disease                                 

• Naoki Kumashiroa,b,
• Derek M. Eriona,b,c,
• Dongyan Zhanga,
• Mario Kahnb,
• Sara A. Beddowb,
• Xin Chud,
• Christopher D. Stilld,
• Glenn S. Gerhardd,
• Xianlin Hane,
• James Dziurab,
• Kitt Falk Petersenb,
• Varman T. Samuelb,f,1, and
• Gerald I. Shulmana,b,c,1
  

+ Author Affiliations

                  

• aHoward Hughes Medical Institute and
• Departments of bInternal Medicine and
• cCellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510;
• dWeis Center for Research, Geisinger Clinic, Danville, PA 17822;
• eDiabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827; and
• fVeterans Affairs Medical Center, West Haven, CT 06516
  

                  

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  Contributed by Gerald I. Shulman, August 24, 2011 (sent for review July 22, 2011)

  
  

               
Abstract                  

Insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD) and is a major factor in the pathogenesis of type 2 diabetes. The development of hepatic insulin resistance has been ascribed to multiple causes, including inflammation, endoplasmic reticulum (ER) stress, and accumulation of hepatocellular lipids in animal models of NAFLD. However, it is unknown whether these same cellular mechanisms link insulin resistance to hepatic steatosis in humans. To examine the cellular mechanisms that link hepatic steatosis to insulin resistance, we comprehensively assessed each of these pathways by using flash-frozen liver biopsies obtained from 37 obese, nondiabetic individuals and correlating key hepatic and plasma markers of inflammation, ER stress, and lipids with the homeostatic model assessment of insulin resistance index. We found that hepatic diacylglycerol (DAG) content in cytoplasmic lipid droplets was the best predictor of insulin resistance (R = 0.80, P < 0.001), and it was responsible for 64% of the variability in insulin sensitivity. Hepatic DAG content was also strongly correlated with activation of hepatic PKCε (R = 0.67, P < 0.001), which impairs insulin signaling. In contrast, there was no significant association between insulin resistance and  other putative lipid metabolites or plasma or hepatic markers of inflammation. ER stress markers were only partly correlated with insulin resistance. In conclusion, these data show that hepatic DAG content in lipid droplets is the best predictor of insulin resistance in humans, and they support the hypothesis that NAFLD-associated hepatic insulin resistance is caused by an increase in hepatic DAG content, which results in activation of PKCε.                  

               
Footnotes                  

• 1To whom correspondence may be addressed. E-mail: [email protected] or [email protected].
  

                  

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  Author contributions: N.K., K.F.P., V.T.S., and G.I.S. designed research; N.K., D.M.E., D.Z., M.K., S.A.B., X.C., C.D.S.,  G.S.G., and X.H. performed research; X.C., C.D.S., G.S.G., X.H., and J.D. contributed new reagents/analytic tools; N.K., D.M.E.,                 D.Z., M.K., S.A.B., C.D.S., G.S.G., X.H., J.D., K.F.P., V.T.S., and G.I.S. analyzed data; and N.K., G.S.G., K.F.P., V.T.S., and G.I.S. wrote the paper.                        

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  The authors declare no conflict of interest.

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  This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1113359108/-/DCSupplemental.                        

  
  

               

StephenW

[谷歌翻译是不是100％正确，仅供参考使用]

摘要

胰岛素抵抗与非酒精性脂肪性肝病（NAFLD）是在2型糖尿病发病的主要因素。肝胰岛素抵抗的发展，已经由于多种原因，包括炎症，内质网（ER）的压力，并积累在脂肪肝动物模型肝癌血脂。然而，它是未知是否这些相同的蜂窝机制链接胰岛素抵抗在人类肝细胞脂肪变性。为了研究细胞机制，链接脂肪肝胰岛素抵抗，我们全面评估这些途径，通过使用闪光灯冷冻肝活检获得从37肥胖，非糖尿病个体和关联的关键肝和血浆标记的炎症，内质网压力，和血脂与稳态模型评估的胰岛素抵抗指数。我们发现，肝甘油二酯（DAG）在细胞质内脂滴的内容是最好的预测胰岛素抵抗（R =0.80，P<0.001），它是负责64％的胰岛素敏感性的变化。肝DAG的内容也强烈相关肝激活PKCε（R= 0.67，P<0.001），损害胰岛素信号。相比之下，有胰岛素抵抗和其他公认的血脂代谢物或血浆或肝脏的炎症标志物之间没有显着的关联。 ER应激标志物，只有部分与胰岛素抵抗密切相关。总之，这些数据表明，脂滴肝DAG的内容，是在人类胰岛素抵抗最好的预测，他们的支持，增加肝DAG的内容引起的脂肪肝相关的肝胰岛素抵抗的假说，这会导致激活PKCε。