Does Diacylglycerol Accumulation in Fatty Liver Disease Cause Hepatic Insulin Resistance?

Brian N Finck,Angela M Hall

doi:10.1155/2015/104132

Abstract

Numerous studies conducted on obese humans and various rodent models of obesity have identified a correlation between hepatic lipid content and the development of insulin resistance in liver and other tissues. Despite a large body of the literature on this topic, the cause and effect relationship between hepatic steatosis and insulin resistance remains controversial. If, as many believe, lipid aggregation in liver drives insulin resistance and other metabolic abnormalities, there are significant unanswered questions as to which lipid mediators are causative in this cascade. Several published papers have now correlated levels of diacylglycerol (DAG), the penultimate intermediate in triglyceride synthesis, with development of insulin resistance and have postulated that this occurs via activation of protein kinase C signaling. Although many studies have confirmed this relationship, many others have reported a disconnect between DAG content and insulin resistance. It has been postulated that differences in methods for DAG measurement, DAG compartmentalization within the cell, or fatty acid composition of the DAG may explain these discrepancies. The purpose of this review is to compare and contrast some of the relevant findings in this area and to discuss a number of unanswered questions regarding the relationship between DAG and insulin resistance.

Highlights

Hepatic insulin resistance, lipid accumulation, and inflammation seem to be tightly interconnected
Hormone sensitive lipase (HSL) deficient mice exhibit increased hepatic insulin sensitivity with reduced hepatic triglyceride content [30, 48], while adenoviral-mediated overexpression of HSL reduced hepatic steatosis [49]. It is not clear whether hepatic DAG content was affected by HSL loss or gain of function, and the evidence provided by these studies may not inform us about the linkage between DAG and insulin resistance
The review of the relevant literature focused on enzymes that directly synthesize or metabolize DAG reveals a pattern of findings that is extremely mixed

Summary

Introduction

Lipid accumulation, and inflammation seem to be tightly interconnected. The biophysical properties and the physiological effects of DAG can be strongly influenced by the composition of the fatty acyl groups and its physical location within the cell. Acyl moieties can be esterified at either the sn-1,2 or the sn-1,3 positions of glycerol depending upon the pathway used to generate the DAG molecule. These two stereoisomers have different biophysical properties in membranes and previous work has shown that the sn-1,2 stereoisomer is much more potent, compared to sn-1,3-DAG, at activating certain signaling cascades linked to insulin resistance [4]. Evidence that the abundance of DAG in the various intracellular compartments (membrane versus lipid droplet) can be more strongly associated with insulin resistance [5, 6]

Connections between DAG and Insulin Resistance

Mechanisms for DAG Synthesis

Mechanisms for DAG Degradation

Conclusions