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Review
. 2017 Jul;38(7):649-665.
doi: 10.1016/j.tips.2017.04.004. Epub 2017 May 24.

Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance

Max C Petersen  1 , Gerald I Shulman  2
Affiliations
Review

Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance

Max C Petersen et al. Trends Pharmacol Sci. 2017 Jul.

Abstract

Although ample evidence links hepatic lipid accumulation with hepatic insulin resistance, the mechanistic basis of this association is incompletely understood and controversial. Diacylglycerols (DAGs) and ceramides have emerged as the two best-studied putative mediators of lipid-induced hepatic insulin resistance. Both lipids were first associated with insulin resistance in skeletal muscle and were subsequently hypothesized to mediate insulin resistance in the liver. However, the putative roles for DAGs and ceramides in hepatic insulin resistance have proved more complex than originally imagined, with various genetic and pharmacologic manipulations yielding a vast and occasionally contradictory trove of data to sort. In this review we examine the state of this field, turning a critical eye toward both DAGs and ceramides as putative mediators of lipid-induced hepatic insulin resistance.

Keywords: ceramide; ectopic lipid; insulin receptor kinase; insulin resistance; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; protein kinase C epsilon.

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Conflict of interest statement

Conflicts of interest

The authors declare that there are no known conflicts of interest associated with this publication.

Figures

Figure 1
Figure 1. The DAG-PKCε-INSR axis in lipid-induced hepatic insulin resistance
In subjects with increased intrahepatic triglyceride (IHTG), sn-1,2-diacylglycerol (DAG) accumulates. DAG activates protein kinase C (PKC) isoforms, and activation of the ε isoform (PKCε) is most consistently observed in insulin-resistant liver. PKCε phosphorylates insulin receptor (INSR) Thr1160, resulting in inhibition of INSR tyrosine kinase activity. All downstream arms of hepatocellular insulin signaling, including stimulation of net glycogen synthesis, transcriptional upregulation of de novo lipogenic genes, and transcriptional downregulation of gluconeogenic genes, are predicted to be affected by this mechanism.
Figure 2
Figure 2. Ceramides in lipid-induced hepatic insulin resistance
Studies in cultured cells have identified two putative direct mechanisms for ceramide-induced insulin resistance. In one, ceramide activation of protein kinase C-ζ (PKCζ) impairs translocation of AKT to the plasma membrane, preventing AKT from participating in insulin action. In the other, ceramide activation of protein phosphatase 2A leads to dephosphorylation and inactivation of AKT. The relevance of these mechanisms to hepatocellular insulin resistance has not been thoroughly investigated. Long-chain ceramides may also promote hepatic lipid accumulation. Promoting ceramide degradation, either through forced expression of acid ceramidase or through harnessing the intrinsic ceramidase activity of the adiponectin receptor (AdipoR) has been shown to improve multiple metabolic parameters in mice.
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