Chronopharmacology of simvastatin on hyperlipidaemia in high-fat diet-fed obese mice

Autor: Anjara Rabearivony, Siyu Chen, Wenxiang Zhang, Xiaofei An, Huan Li, Chang Liu
Rok vydání: 2020
Předmět:
0301 basic medicine
Drug
Male
Simvastatin
media_common.quotation_subject
Hypercholesterolemia
Mice
Obese
Hyperlipidemias
Pharmacology
Diet
High-Fat
03 medical and health sciences
Mice
Random Allocation
0302 clinical medicine
Chronopharmacokinetics
In vivo
Circadian Clocks
Hyperlipidemia
polycyclic compounds
Zeitgeber
medicine
Animals
cardiovascular diseases
Circadian rhythm
RNA
Messenger
Adverse effect
media_common
business.industry
Circadian Rhythm Signaling Peptides and Proteins
Drug Chronotherapy
nutritional and metabolic diseases
Cell Biology
medicine.disease
PER2
030104 developmental biology
Gene Expression Regulation
Liver
030220 oncology & carcinogenesis
Molecular Medicine
lipids (amino acids
peptides
and proteins)
Hydroxymethylglutaryl-CoA Reductase Inhibitors
business
medicine.drug
Zdroj: Journal of cellular and molecular medicine. 24(18)
ISSN: 1582-4934
Popis: The chronopharmacology refers to the utilization of physiological circadian rhythms to optimize the administration time of drugs, thus increasing their efficacy and safety, or reducing adverse effects. Simvastatin is one of the most widely prescribed drugs for the treatment of hypercholesterolaemia, hyperlipidemia and coronary artery disease. There are conflicting statements regarding the timing of simvastatin administration, and convincing experimental evidence remains unavailable. Thus, we aimed to examine whether different administration times would influence the efficacy of simvastatin. High-fat diet-fed mice were treated with simvastatin at zeitgeber time 1 (ZT1) or ZT13, respectively, for nine weeks. Simvastatin showed robust anti-hypercholesterolaemia and anti-hyperlipidemia effects on these obese mice, regardless of administration time. However, simvastatin administrated at ZT13, compared to ZT1, was more functional for decreasing serum levels of total cholesterol, triglycerides, non-esterified free fatty acids and LDL cholesterol, as well as improving liver pathological characteristics. In terms of possible mechanisms, we found that simvastatin did not alter the expression of hepatic circadian clock gene in vivo, although it failed to change the period, phase and amplitude of oscillation patterns in Per2::Luc U2OS and Bmal1::Luc U2OS cells in vitro. In contrast, simvastatin regulated the expression of Hmgcr, Mdr1 and Slco2b1 in a circadian manner, which potentially contributed to the chronopharmacological function of the drug. Taken together, we provide solid evidence to suggest that different administration times affect the lipid-lowering effects of simvastatin.
Databáze: OpenAIRE
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