Regulation of hepatic neutral cholesteryl ester hydrolase by hormones and changes in cholesterol flux.
To understand molecular events in regulation of hepatic neutral cholesteryl ester hydrolase (EC3.1.1.13; CEH), catalytic activity, protein mass, and mRNA levels were measured in rats with various perturbations of hepatic cholesterol metabolism. Cholesterol feeding decreased activity (56 +/- 2%), mass (44 +/- 2%), and mRNA (14 +/- 3%). The cholesterol precursor mevalonate also decreased activity (42 +/- 6%), mass (76 +/- 3%), and mRNA (23 +/- 16%). Inhibition of cholesterol biosynthesis by lovastatin increased activity (65 +/- 12%) and mRNA (31 +/- 24%). Stimulation of cholesterol efflux by chronic biliary diversion increased activity (138 +/- 34%), mass (29 +/- 7%), and mRNA (146 +/- 28%). Chenodeoxycholate feeding decreased activity (46 +/- 6%) and mRNA (26 +/- 12%). These data suggest rational regulation of CEH in response to changes in cholesterol flux through the liver. In primary hepatocytes, steady-state mRNA markedly decreased during 72-h cultures and addition of L-thyroxine and dexamethasone synergistically maintained mRNA levels near control values. Lovastatin increased mRNA levels by 103 +/- 15%. Taurocholate and phorbol 12-myristate 13-acetate suppressed mRNA (61 +/- 4% and 49 +/- 13%, respectively), suggesting that protein kinase C mediated effects of bile acids on CEH mRNA levels. These data suggest regulation of CEH by hormones and signal transduction in addition to changes in cholesterol flux.
Ghosh
S
S
Department of Biochemistry, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
Natarajan
R
R
Pandak
W M
WM
Hylemon
P B
PB
Grogan
W M
WM
D000818:Animals; D001647:Bile Acids and Salts / Q000008:administration & dosage / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004032:Diet; D005938:Glucocorticoids / Q000494:pharmacology; D006728:Hormones / Q000502:physiology*; D007425:Intracellular Membranes / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*; D013974:Thyroxine / Q000494:pharmacology
D001647:Bile Acids and Salts; D005938:Glucocorticoids; D006728:Hormones; D012333:RNA, Messenger; D003907:Dexamethasone; D002784:Cholesterol; D002787:Sterol Esterase; D013974:Thyroxine