S-alk(en)yl cysteines of garlic inhibit cholesterol synthesis by deactivating HMG-CoA reductase in cultured rat hepatocytes.
The effects of water-soluble organosulfur compounds of garlic on hepatic cholesterol biosynthesis in cultured rat hepatocytes were studied. S-Alk(en)yl cysteines, i.e., S-allyl cysteine (SAC), S-ethyl cysteine (SEC) and S-propyl cysteine (SPC) inhibited cholesterol synthesis from [(14)C]acetate but not from [(14)C]mevalonate. The activity of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase in the cells treated with SAC, SEC and SPC was 30-40% lower than that of the untreated cells. S-Alk(en)yl cysteines did not alter abundance of mRNA coded for HMG-CoA reductase or protein concentration of the enzyme. The ratio of expressed to total activity (E/T) of HMG-CoA reductase was then determined as an index of phosphorylation status of the enzyme. The E/T ratio was reduced 18-29% by SAC, SEC and SPC, resulting primarily from decreased expressed activity. The results suggest that S-alk(en)yl cysteines inhibit cholesterol synthesis by deactivating HMG-CoA reductase via enhanced phosphorylation, but not changing levels of mRNA or the amount of the enzyme. Additionally, of the three S-alk(en)yl cysteines tested, only SAC appears to further decrease the activity of HMG-CoA reductase by increasing sulfhydryl oxidation of the enzyme.
Liu
Lijuan
L
Nutrition Department, The Pennsylvania State University, University Park, PA 16802, USA.
Yeh
Yu-Yan
YY
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002247:Carbon Isotopes; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005737:Garlic / Q000737:chemistry; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000924:Anticholesteremic Agents; D002247:Carbon Isotopes; D012333:RNA, Messenger; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D003545:Cysteine