The metabolic cascade leading to eicosanoid precursors – desaturases, elongases, and phospholipases A2 – is altered in Zucker fatty rats

Metabolic syndrome characterized by insulin resistance and obesity is accompanied by severe lipid metabolism perturbations and chronic low-grade inflammation. However, many unresolved questions remained regarding the regulation that underlie dyslipidemia, particularly the regulation of the metabolic cascade (synthesis and release) leading to eicosanoid precursors release. This study was undertaken to investigate the regulation of desaturases/elongases and phospholipases A2 during the establishment of metabolic syndrome. Our results showed that delta-6 desaturase as well as elongase-6 expressions were upregulated in 3-month-old Zucker fatty rats as compared to lean littermates, independently of SREBP-1c activation. We also demonstrated for the first time an increase of liver group VII phospholipase A2 gene expression in the obese animals together with a strong specific inhibition of type IVA and VIA phospholipases A2. These results suggest that the regulation of unsaturated fatty acids biosynthesis and signalling cascade could contribute to the development of liver lipid dysregulation related to metabolic syndrome and may be considered as new potential targets in such pathological conditions.

Research Highlights
► Liver lipid metabolism was studied in Zucker rats, model of metabolic syndrome.
► We observed a marked increase of liver saturated and mono-unsaturated fatty acids.
► SCD-1 and D6D were increased independently of SREBP-1c in fatty rats.
► Elongase-6 gene expression was specifically upregulated.
► Expression of type IVA and VIA PLA2 was specifically decreased in obese animals.