Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

Abstract

Sphingolipid turnover has been shown to be activated at old age and in response to various stress stimuli including oxidative stress. Reduction of vitamin E content in the liver under the pro-oxidant action is associated with enhanced sphingolipid turnover and ceramide accumulation in hepatocytes. In the present paper, the correction of sphingolipid metabolism in the liver cells of old rats and in the palmitate-treated young hepatocytes using α-tocopherol has been investigated. 3-and 24-month-old rats, [ 14 C] palmitic acid, [methyl− 14 C-choline]sphingomyelin (SM), and [ 14 C]serine were used. α-Tocopherol administration to old rats or addition to the culture medium of old liver slices or hepatocytes prevented age-dependent increase of ceramide synthesis and lipid accumulation, and increased SM content in liver tissue and cells. α-Tocopherol treatment of old cells decreased the neutral and acid sphingomyelinase (SMase) activities in hepatocytes and serine palmitoyl transferase activity in the liver cell microsomes. Effect of α-or γ-tocopherol, but not of δ-tocopherol, on the newly synthesized ceramide content in old cells was correlated with the action of inhibitor of serine palmitoyl transferase (SPT) activity (myriocin) and SMase inhibitors (glutathione, imipramine). Addition of α-tocopherol as well as myriocin to the culture medium of young hepatocytes, treated by palmitate, abolished ceramide accumulation and synthesis. The data obtained demonstrate that α-tocopherol normalized elevated ceramide content in the old liver cells via inhibition of acid and neutral SMase activities and lipid synthesis de novo. α-Tocopherol, reducing ceramide synthesis, prevented palmitate-induced aging-like ceramide accumulation in young liver cells.

Sex Differences in Cardiovascular Diseases: A Matter of Estrogens, Ceramides, and Sphingosine 1-Phosphate

“…The specific mechanism behind these differences has not been thoroughly investigated. However, as seen throughout this review, clinical and pre-clinical studies suggest a pivotal role of SL metabolism and levels, which per previous experimental studies in vitro and in vivo in rats are modulated by Es and also by the aforementioned antioxidant molecules [ 191 , 192 ], as predictors of the CV risk in a sex-specific manner. Notably, the role of these molecules is constructive, particularly when correlated with E and PhE levels.…”

Spinal Cord Injury Causes Chronic Liver Pathology in Rats

“…Treatment with vitamin E can reduce ceramide accumulation in the brain and liver. 45,46 In the liver, this reduction in ceramide levels by vitamin E occurs, at least in part, through inhibition of both SPT and sphingomyelinase. 46 In this way, vitamin E inhibits two pathways of ceramide synthesis and thereby may prevent ceramide elevation in the liver at 21 dpi despite increased SPT mRNA.…”

“…45,46 In the liver, this reduction in ceramide levels by vitamin E occurs, at least in part, through inhibition of both SPT and sphingomyelinase. 46 In this way, vitamin E inhibits two pathways of ceramide synthesis and thereby may prevent ceramide elevation in the liver at 21 dpi despite increased SPT mRNA. Ceramide production is also induced by inflammatory cytokines, such as TNF-a and IL-1b, 44 both of which are increased after SCI and may contribute to ceramide formation through the induction of hydrolytic or recycling pathways, although this remains to be determined.…”