Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease

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.

Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance

“…The expression of neither Mlycd nor Dgat2 was modified in liver of CypD-KO mice compared with WT mice. Altogether, these results suggest that lipid accumulation in liver of CypD-KO mice is likely related to both a [16][17][18][19][20][21][22][23][24][25] reduction in lipid oxidation and an increase in lipid storage, the latter being mainly associated with increased de novo lipogenesis.…”

“…Indeed, both induction of ER stress and accumulation of intracellular lipids have been involved in hepatic insulin resistance. Activation of JNK has been shown in ER stress-mediated hepatic insulin resistance [20] and activation of PKCε has been related to DAG-induced hepatic insulin resistance [23]. In CypD-KO mice, hepatic insulin resistance appears to be mainly secondary to ER stress modulation of hepatic lipogenesis and subsequent DAG-mediated activation of PKCε rather than to ER stressinduced JNK activation, at least in vitro.…”

“…Role of PKCε in CYPD-related alteration of insulin signalling Both JNK and PKCε enzymes, which are increased in liver of CypD-KO mice, are potential mediators of hepatic insulin resistance [20,23]. To discriminate between the two, we measured the effect of CYPD silencing on insulinstimulated PKB phosphorylation in the presence or absence of JNK and PKCε inhibitors.…”

“…7e), were significantly increased in the liver of CypD-KO mice. As PKCε was shown to be involved in DAG-mediated hepatic insulin resistance [23], we analysed its activity by measuring its translocation from cytosol to membrane. Consistent with DAG accumulation, PKCε activity was induced in the livers of CypD-KO mice (Fig.…”

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…2), which further inhibits the insulin receptor and its downstream signaling (Samuel et al, 2004). Moreover, in obese non diabetic humans with NAFLD, Kumashiro et al, could show that hepatic diacylglycerol content was the best predictor of insulin resistance, when assessed by the HOMA index (Kumashiro et al, 2011). However, whether insulin resistance promotes hepatic lipid accumulation or whether NAFLD initiates insulin resistance remains unclear to date.…”