Oleic acid is a potent inhibitor of fatty acid and cholesterol synthesis in C6 glioma cells

Abstract

Glial cells play a pivotal role in brain fatty acid metabolism and membrane biogenesis. However, the potential regulation of lipogenesis and cholesterologenesis by fatty acids in glial cells has been barely investigated. Here, we show that physiologically relevant concentrations of various saturated, monounsaturated, and polyunsaturated fatty acids significantly reduce [1-14 C]acetate incorporation into fatty acids and cholesterol in C6 cells. Oleic acid was the most effective at depressing lipogenesis and cholesterologenesis; a decreased label incorporation into cellular palmitic, stearic, and oleic acids was detected, suggesting that an enzymatic step(s) of de novo fatty acid biosynthesis was affected. To clarify this issue, the activities of acetylcoenzyme A carboxylase (ACC) and FAS were determined with an in situ digitonin-permeabilized cell assay after incubation of C6 cells with fatty acids. ACC activity was strongly reduced (?80%) by oleic acid, whereas no significant change in FAS activity was observed. Oleic acid also reduced the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). The inhibition of ACC and HMGCR activities is corroborated by the decreases in ACC and HMGCR mRNA abundance and protein levels. The downregulation of ACC and HMGCR activities and expression by oleic acid could contribute to the reduced lipogenesis and cholesterologenesis.-Natali, F., L. Siculella, S. Salvati, and G. V. Gnoni. Oleic acid is a potent inhibitor of fatty acid and cholesterol synthesis in C6 glioma cells. J. Lipid Res. 2007Res. . 48: 1966Res. -1975. After white adipose tissue, the brain is the organ with the highest lipid content of the body. The biosynthesis and deposition of lipids play an important role in maintaining brain structure and function, for example, during development-associated biogenesis of neural cell membranes. It is well established that alterations in lipid metabolism are the cause of or are associated with many neurological diseases (1-3).Astrocytes, the major class of glial cells in the mammalian brain, play an active role in brain metabolism. These cells surround intraparenchymal blood capillaries so that they represent the first cellular barrier for nutrients and other substances entering the brain system. A metabolic coupling between astrocytes and neurons to maintain energy metabolism homeostasis has been described (4, 5). Metabolic regulation in the brain has been investigated extensively, and those studies focused mostly on carbohydrate and amino acid metabolism (for review, see Ref. 6). During neuronal activity, glucose taken up by astrocytes is converted into lactate, which is then released into the extracellular space to be used by neurons (6). Regarding lipid metabolism, astroglial ketone body synthesis, showing characteristics strikingly similar to those of hepatic ketogenesis (7), may represent an important pathway for brain energy production and/or biosynthetic processes. The involvement of fatty acids in cell death pathways, particularly in the con...

Detection of Metabolite Changes in C6 Glioma Cells Cultured with Antimitotic Oleyl Glycoside by 1H MAS NMR

“…A recent report showed that oleic acid strongly reduced acetyl-CoA carboxylase activity and was an inhibitor of fatty acid synthesis in C6 glioma cells. 22 Interestingly, compound 1 is a glycoside of oleyl alcohol, and the presence of the oleyl group was the main structural difference with respect to the parent glycosides that resulted less inhibitory of glioma cell division than 1. 7 The treatment of C6 cells with oleic acid (100 µM) for 24 h afforded a 1 H NMR spectrum similar to that obtained with 1 (10 µM) (Figure 1c), in which the major metabolic change was also the intensity of the signal at 0.67 ppm.…”

Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes

“…After incubated for 48 h, cells were treated with LY294002 (0, 10, 20, 30, 40, 50 μmol/l), rapamycin (1, 10, 30, 50, 90 nmol/l) and NVP-BEZ235 (0.1, 1, 10, 500, 1000, 2000 nmol/l). The viability was examined at incubation for 6, 12, 24, 36 h according to the process by Natali (Natali et al, 2007). Cell monolayers were incubated for 4 h with 1 mg/ml MTT (Beyotime, Jiangsu, China), which is converted from the yellow tetrazolium compound to the purple formazan derivative by mitochondria of living cells.…”

Increased brain uptake and oxidation of acetate in heavy drinkers

“…Consumption of enough alcohol to achieve breath alcohol levels of even 50 mg% is sufficient for plasma acetate levels to approach 1-2 mM, beyond which the plasma acetate concentration does not rise (6,9,10,12,13). Acetate travels to other organs, including the brain, for use as an energy substrate (14) and in fatty acid and cholesterol biosynthesis (15,16). The conversion of ethanol to acetate begins with metabolism to acetaldehyde.…”