Atorvastatin increases hepatic fatty acid beta-oxidation in sucrose-fed rats: comparison with an MTP inhibitor.
We investigated the effects of atorvastatin, a widely used 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and BMS-201038, a microsomal triglyceride transfer protein (MTP) inhibitor, in sucrose-fed hypertriglyceridemic rats to determine whether the activation of beta-oxidation by these compounds plays a role in their hypotriglyceridemic effect. The decrease in plasma triglyceride concentration and post-Triton very low-density lipoprotein (VLDL) triglyceride concentration, a measure of hepatic triglyceride secretion, by atorvastatin (30 mg/kg p.o.) for 2 weeks was to approximately the same degree as those by BMS-201038 (0.3 mg/kg). Atorvastatin (30 mg/kg) increased hepatic beta-oxidation activity by 54% (P < 0.01), while BMS-201038 (0.3 mg/kg) had no significant effect. Atorvastatin decreased hepatic triglyceride, fatty acid and cholesteryl ester concentrations by 21% to 39%, whereas BMS-201038 increased these variables by 28% to 307%. In the atorvastatin-treated groups, a significant relationship was seen not only between hepatic beta-oxidation activity and hepatic triglyceride concentration (R(2) = 0.535, P < 0.01), but also between hepatic and plasma triglyceride concentrations (R(2) = 0.586, P < 0.01). No effect of atorvastatin on hepatic fatty acid synthesis was observed. These results indicate that the activation of hepatic beta-oxidation by atorvastatin may contribute to the decrease in hepatic triglyceride concentration, leading to its hypotriglyceridemic effect.
Funatsu
Toshiyuki
T
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co, Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 3058585, Japan. funatsu@yamanouchi.co.jp
Kakuta
Hirotoshi
H
Takasu
Toshiyuki
T
Miyata
Keiji
K
D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D000069059:Atorvastatin; D001562:Benzimidazoles / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002784:Cholesterol / Q000096:biosynthesis; D005227:Fatty Acids / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D050356:Lipid Metabolism; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013395:Sucrose / Q000008:administration & dosage*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D001055:Apolipoproteins B; C473731:BMS201038; D001562:Benzimidazoles; D002352:Carrier Proteins; D005227:Fatty Acids; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008079:Lipoproteins, VLDL; D011758:Pyrroles; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D013395:Sucrose; D002784:Cholesterol; D000069059:Atorvastatin