Stimulation of autophagy by antilipolytic drugs may rescue rodents from age-associated hypercholesterolemia.
Aging is characterized by several metabolic changes responsible for the decline of certain functions and the appearance of age-related diseases, including hypercholesterolemia, which is the main risk factor for atherosclerosis and cardiovascular disease. Similar changes in a number of morphological and biochemical parameters were observed in rats. Caloric restriction (CR) was shown to increase longevity and prevent age-related diseases in various organisms, and to counteract the age-associated increase in plasma cholesterol. CR was thought to operate through the stimulation of the process of macroautophagy. The aim of this work was to investigate the effect of the stimulation of macroautophagy on age-associated cholesterolemia. Mature Sprague-Dawley rats were fasted overnight and given the antilipolytic agent 3,5-dimethylpyrazole (DMP; 12 mg/kg b.w. in 0.2 mL of saline, intraperitoneally). The age-related changes in cholesterol plasma level, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA-R) activity, and lipoperoxidation were determined. Low-density lipoprotein (LDL) receptor expression was determined by immunoblot of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE)-separated liver membranes. Results show that the stimulation of macroautophagy reduces the total LDL and high-density lipoprotein (HDL) cholesterol plasma level to juvenile values, and triglycerides levels even lower. The hypocholesterolemic action of DMP requires neither the counteraction of the age-related changes in the HMG-CoA-R activation state and regulation, nor the counteraction of the age-related increase in lipoperoxidation, and only involves a restoration of the numbers of LDL receptors on liver membranes to juvenile levels.
Centro di Ricerca di Biologia e Patologia dell'Invecchiamento, Università di Pisa, Pisa, Italy.
Sara
S
Straniero
Gabriella
G
Cavallini
Alessio
A
Donati
Valentina
V
Pallottini
Chiara
C
Martini
Anna
A
Trentalance
Ettore
E
Bergamini
D000375:Aging / Q000097:blood / Q000187:drug effects* / Q000473:pathology*; D000597:Amino Acids, Branched-Chain / Q000097:blood; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002457:Cell Extracts; D004789:Enzyme Activation / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006937:Hypercholesterolemia / Q000097:blood / Q000201:enzymology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D008055:Lipids / Q000097:blood; D008066:Lipolysis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D013997:Time Factors
D000597:Amino Acids, Branched-Chain; D002457:Cell Extracts; D008055:Lipids; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; D006903:Hydroxymethylglutaryl CoA Reductases; C027635:3,5-dimethylpyrazole