title: Effect of procysteine on aging-associated changes in hepatic GSH and SMase: evidence for transcriptional regulation of smpd3.
abstract: In hepatocytes, aging-associated decline in GSH has been linked to activation of neutral SMase (nSMase), accumulation of bioactive ceramide, and inflammation. In this study, we seek to test whether dietary supplementation with the cysteine precursor, L-2-oxothiazolidine-4-carboxylic acid (OTC), would correct the aging-associated differences in hepatic GSH, nSMase, and ceramide. Young and aged mice were placed on a diet that either lacked sulfur-containing amino acids (SAAs) or had 0.5% OTC for 4 weeks. Mice fed standard chow were used as an additional control. SAA-deficient mice exhibited significant aging-associated differences in hepatic GSH, GSH/GSSG, ceramide, and nSMase. C24:1 ceramide, the major ceramide species in liver, was affected the most by aging, followed by the less abundant C16:0 ceramide. OTC supplementation eliminated the aging-associated differences in hepatic GSH and GSH/GSSG ratio. Surprisingly, however, instead of decreasing, the nSMase activity and ceramide increased in the OTC-fed mice irrespective of their age. These effects were due to elevated nSMase-2 mRNA and protein and appeared to be direct. Similar increases were seen in HepG2 cells following treatment with OTC. The OTC-fed aged mice also exhibited hepatic steatosis and triacylglyceride accumulation. These results suggest that OTC is a potent stimulant of nSMase-2 expression and that there may be unanticipated complications of OTC supplementation.
authors.affiliation: Department of Physiology, A. B. Chandler Medical Center, University of Kentucky, Lexington, KY 40536.
authors.forename: Gergana
authors.initials: G
authors.lastname: Deevska
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, Lexington Veterans Affairs Medical Center, Lexington, KY 40536.
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.affiliation: Department of Physiology, A. B. Chandler Medical Center, University of Kentucky, Lexington, KY 40536.
authors.forename: Claudia
authors.initials: C
authors.lastname: Karakashian
authors.affiliation: Department of Physiology, A. B. Chandler Medical Center, University of Kentucky, Lexington, KY 40536.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Peppers
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, Lexington Veterans Affairs Medical Center, Lexington, KY 40536.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.affiliation: Department of Physiology, A. B. Chandler Medical Center, University of Kentucky, Lexington, KY 40536.
authors.forename: Mariana N
authors.initials: MN
authors.lastname: Nikolova-Karakashian
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002518:Ceramides / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D011761:Pyrrolidonecarboxylic Acid / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013108:Sphingomyelin Phosphodiesterase / Q000096:biosynthesis*; D053778:Thiazolidines / Q000494:pharmacology*
chemical_list: D002518:Ceramides; D012333:RNA, Messenger; D053778:Thiazolidines; C491484:SMPD3 protein, human; C491483:Smpd3 protein, mouse; D013108:Sphingomyelin Phosphodiesterase; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid
keywords: aging; ceramide; diet; neutral Sphingomyelinase-2; oxidative stress; reduced glutathione supplementation; sphingomyelinase