FADS2 inhibition in essential fatty acid deficiency induces hepatic lipid accumulation via impairment of very low-density lipoprotein (VLDL) secretion.

Fatty acid desaturase 2 (FADS2) is responsible for the first desaturation reaction in the synthesis of highly unsaturated fatty acids (HUFAs), such as arachidonic acid (20:4n-6) and eicosapentaenoic acid (20:5n-3), and is involved in Mead acid (20:3n-9) production during essential fatty acid deficiency (EFAD). In this study, an obvious hepatic lipid accumulation was observed in EFAD mice treated with a FADS2 inhibitor. FADS2 inhibition in the EFAD state reduced secretion of very low-density lipoprotein (VLDL) and markedly diminished Mead acid in phosphatidylcholine (PC) in the liver and plasma. As the results, the amount of C20 HUFAs in hepatic and plasma PC dramatically reduced in the EFAD mice treated with a FADS2 inhibitor, whereas the decrease of C20 HUFA levels of PC in EFAD mice was not observed because of the increased Mead acid in PC. These results supposed that Mead acid in PC is important as a component of VLDL. It is possible that Mead acid plays the role of a substitute of HUFAs in VLDL secretion during EFAD.

Amadori-modified glycated albumin predominantly induces E-selectin expression on human umbilical vein endothelial cells through NADPH oxidase activation.

BACKGROUND: Protein glycation is closely linked to endothelial-cell dysfunction and vascular complications in diabetes. Glycated albumin is reported to induce cellular signaling similar to advanced glycation endoproducts (AGEs), however, cellular signaling remains obscure. METHOD: We stimulated human umbilical vein endothelial cells (HUVECs) by glycated human serum albumin (Glc-HSA), determined E-selectin expression by real-time PCR and immunometric methods, and estimated cellular signaling by using various signaling molecule inhibitors and confocal microscopy. RESULTS: Glc-HSA-induced E-selectin expression was 10 or 20 times more than that induced with 3 kinds of AGEs-HSAs, which was not suppressed by anti-receptor for AGEs (RAGE) antibody. Glc-HSA-induced E-selectin expression was completely suppressed by the NADPH oxidase inhibitor diphenylene iodonium chloride and the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine. Confocal microscopic analysis also revealed intracellular accumulation of ROS. Glc-HSA-induced E-selectin expression was suppressed by the phosphatidylinositol 3 kinase (PI3K) inhibitors wortmannin and LY294002, the protein kinase B (PKB) inhibitor ML-9, the IkappaB kinase (IKK) inhibitor BAY117082, and the Jun N-terminal kinase (JNK) inhibitor SP600125, On the other hand, the protein kinase C inhibitors calphostin C and H-7 did not suppress Glc-HSA-induced E-selectin expression. CONCLUSION: Glc-HSA induces activation of NADPH oxidase, PKB-IKK and JNK, then E-selectin gene transcription is upregulated by nuclear-translocated NF-kappaB and AP-1.