Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease

被引:447
|
作者
Kumashiro, Naoki [1 ,2 ]
Erion, Derek M. [1 ,2 ,3 ]
Zhang, Dongyan [2 ]
Kahn, Mario [1 ]
Beddow, Sara A. [1 ]
Chu, Xin [4 ]
Still, Christopher D. [4 ]
Gerhard, Glenn S. [4 ]
Han, Xianlin [5 ]
Dziura, James [1 ]
Petersen, Kitt Falk [1 ]
Samuel, Varman T. [1 ,6 ]
Shulman, Gerald I. [1 ,2 ,3 ]
机构
[1] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA
[2] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA
[3] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA
[4] Weis Ctr Res, Geisinger Clin, Danville, PA 17822 USA
[5] Sanford Burnham Med Res Inst, Diabet & Obes Res Ctr, Orlando, FL 32827 USA
[6] Vet Affairs Med Ctr, West Haven, CT 06516 USA
关键词
PROTEIN-KINASE-C; ENDOPLASMIC-RETICULUM STRESS; HEPATIC STEATOSIS; METABOLIC SYNDROME; CERAMIDE SYNTHESIS; SKELETAL-MUSCLE; OBESE SUBJECTS; TISSUE; TRIGLYCERIDE; ACTIVATION;
D O I
10.1073/pnas.1113359108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 PKCe (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 PKCe.
引用
收藏
页码:16381 / 16385
页数:5
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