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Biochim Biophys Acta. 2016 Nov;1861(11):1828-1839. doi: 10.1016/j.bbalip.2016.08.016. Epub 2016 Aug 31.

Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species.

Author information

1
Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia.
2
School of Medicine, University of Wollongong, Wollongong, NSW, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
3
Prince of Wales Clinical School, UNSW Australia, Sydney, NSW, Australia.
4
School of Mathematics and Statistics, UNSW Australia, Sydney, NSW, Australia.
5
Diabetes & Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Australia, Sydney, NSW, Australia.
6
Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia. Electronic address: n.turner@unsw.edu.au.

Abstract

In a recent study, we showed that in response to high fat feeding C57BL/6, 129X1, DBA/2 and FVB/N mice all developed glucose intolerance, while BALB/c mice displayed minimal deterioration in glucose tolerance and insulin action. Lipidomic analysis of livers across these five strains has revealed marked strain-specific differences in ceramide (Cer) and sphingomyelin (SM) species with high-fat feeding; with increases in C16-C22 (long-chain) and reductions in C>22 (very long-chain) Cer and SM species observed in the four strains that developed HFD-induced glucose intolerance. Intriguingly, the opposite pattern was observed in sphingolipid species in BALB/c mice. These strain-specific changes in sphingolipid acylation closely correlated with ceramide synthase 2 (CerS2) protein content and activity, with reduced CerS2 levels/activity observed in glucose intolerant strains and increased content in BALB/c mice. Overexpression of CerS2 in primary mouse hepatocytes induced a specific elevation in very long-chain Cer, but despite the overall increase in ceramide abundance, there was a substantial improvement in insulin signal transduction, as well as decreased ER stress and gluconeogenic markers. Overall our findings suggest that very long-chain sphingolipid species exhibit a protective role against the development of glucose intolerance and hepatic insulin resistance.

KEYWORDS:

Ceramide species; Endoplasmic reticulum stress; Insulin sensitivity and resistance; Lipid metabolism; Lipidomics; Obesity

PMID:
27591968
DOI:
10.1016/j.bbalip.2016.08.016
[Indexed for MEDLINE]

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