Abstract
AimThere are few and contradictory data on the role of excessive accumulation of intracellular sphingolipids, particularly ceramides, in the development of hepatic insulin resistance. In our study we assessed accumulated sphingolipid fractions and clarify the mechanisms of hepatic insulin resistance development as well as involvement of fatty acid and ceramide transporters in this process.MethodsIn culture of primary rat hepatocytes, exposed to high concentration of palmitic acid (0.75mM) during short and prolonged incubation, high performance liquid chromatography was used to assess intra- and extracellular sphingolipid fractions content. Degree of palmitate-induced insulin resistance was estimated by measuring changes in phosphorylation of insulin pathway proteins by western blotting as well as changes in expression of different type of transporters.ResultsIn our study short and prolonged exposure of primary hepatocytes to palmitic acid resulted in increased intracellular accumulation of ceramide which inhibited insulin signaling pathway. We observed a significant increase in the expression of fatty-acid transport protein (FATP2) and ceramide transfer protein (CERT) what is consistent with enhanced intracellular ceramide content. The content of extracellular ceramide was increased nearly threefold after short and twofold after long incubation period. Expression of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter (ABCA1) was increased significantly mainly after short palmitate incubation.ConclusionOur data showed that increase in intarcellular ceramide content contributes to the development of hepatic insulin resistance. We suggest pivotal role of transporters in facilitating fatty acid influx (FATP2), accumulation of ceramides (CERT) and export to the media (MTP and ABCA1).
Highlights
The incidence of obesity and type 2 diabetes mellitus is reaching epidemic proportions worldwide
In our study short and prolonged exposure of primary hepatocytes to palmitic acid resulted in increased intracellular accumulation of ceramide which inhibited insulin signaling pathway
We observed a significant increase in the expression of fatty-acid transport protein (FATP2) and ceramide transfer protein (CERT) what is consistent with enhanced intracellular ceramide content
Summary
The incidence of obesity and type 2 diabetes mellitus is reaching epidemic proportions worldwide. Fatty acid storage capacity of adipocytes is exceeded and lipids accumulate in other tissues such as muscles and liver [2,3]. As far most data concerning the relationship of sphingolipids (especially ceramides) and insulin resistance are based on skeletal muscle studies and the molecular mechanisms that underlie hepatic insulin resistance are still not clear [6]. The molecular mechanisms of ceramide-induced insulin resistance are complex and not completely understood, in hepatocytes, there is emerging evidence for fatty acid transport involvement in increased fatty acids influx followed by excessive free fatty acid accumulation [7,8,9]. Recent studies have shown the presence of these transporters in hepatocytes, but the precise mechanism of fatty acid transporters action and their role in liver remains unclear [10]
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