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The fenofibrate effect on genotoxicity in brain and liver and on the expression of genes regulating fatty acids metabolism of mice

2019; Volume: 65; Issue: 5 Linguagem: Inglês

10.18097/pbmc20196505388

2310-6972

Victoria G. Khorolskaya, Artem P. Gureev, Ekaterina A. Shaforostova, D.A. Laver, В. Н. Попов,

Metabolomics and Mass Spectrometry Studies

Fibrates are well-known agonists of the PPAR family (peroxisome proliferator-activated receptors). This class of drugs is used for the treatment of dyslipidemia and atherosclerosis. Fenofibrate is one of the members of this class of synthetic PPARα receptor ligands. The oral administration of 0.3% fenofibrate caused a decrease in strength due to loss of body weight in laboratory animals when improving behavioural features. Analysis of the mitochondrial DNA of liver cells showed a genotoxic effect of fenofibrate, due to accumulation of reactive oxygen species, which could be attributed to activation of peroxisomal β-oxidation processes, as well as to the lack of increase in the expression of genes encoding antioxidant defense proteins. Treatment with fenofibrate did not cause brain mtDNA damage. It has been shown that fenofibrate induced mitochondrial β-oxidation in the brain, as indicated by the increased expression of the Acadm and Cpt1a and Ppargc1a and Ppara. The study found no effect of fenofibrate on the increase of mitochondrial biogenesis in brain and liver cells. Thus, we can conclude that fenofibrate significantly affects lipid metabolism in the liver and brain, but in the liver it is associated with an increase of oxidative stress, resulting in mtDNA oxidative damage. However, fenofibrate-induced increase in the expression of Ppargc1a is not associated with an increase of mitochondrial biogenesis. This is consistent with the recent suggestion that PGC-1α might not be a master regulator of mitochondrial biogenesis.Sredi agonistov semeĭstva PPAR (peroxisome proliferator-activated receptors) khorosho izvesten klass fibratov – veshchestv, ispol'zuemykh v terapii dislipidemii i ateroskleroza. Odnim iz nikh iavliaetsia fenofibrat – sinteticheskiĭ ligand retseptora PPARα. Pri peroral'nom vvedenii 0,26 mg/kg/sut fenofibrata laboratornym zhivotnym obnaruzheno snizhenie ikh vynoslivosti vsledstvie poteri massy tela pri odnovremennom uluchshenii povedencheskikh pokazateleĭ. Issledovanie mitokhondrial'noĭ DNK kletok pecheni vyiavilo genotoksicheskiĭ éffekt fenofibrata, kotoryĭ, predpolozhitel'no, obuslavlivaetsia nakopleniem aktivnykh form kisloroda, chto, veroiatno, sviazano s aktivatsieĭ protsessov peroksisomal'nogo β-okisleniia, a takzhe otsutstviem uvelicheniia ékspressii genov, kodiruiushchikh belki antioksidantnoĭ zashchity. Pri vvedenii fenofibrata ne obnaruzheno povrezhdeniĭ mtDNK v perednem mozge, chto sviazano s aktivnoĭ rabotoĭ antioksidantnoĭ sistemy kletki. Pri étom obnaruzheno povyshenie ékspressii genov, kodiruiushchikh fermenty β-okisleniia (Acadm i Cpt1a), a takzhe Ppargc1a i Ppara, v mozge. V issledovanii ne bylo obnaruzheno vliianiia fenofibrata na uvelichenie intensivnosti mitokhondrial'nogo biogeneza v kletkakh mozga i pecheni. Takim obrazom, mozhno sdelat' vyvod, chto priem fenofibrata znachitel'no vliiaet na ékspressiiu genov, reguliruiushchikh metabolizm lipidov v pecheni i golovnom mozge; v pecheni éto mozhet byt' assotsiirovano s vozrastaniem urovnia okislitel'nogo stressa, kosvennymi markerami kotorogo iavliaiutsia povrezhdeniia mtDNK. Odnako fenofibrat-indutsirovannoe uvelichenie ékspressii Ppargc1a ne assotsiirovano s uvelicheniem intensivnosti mitokhondrial'nogo biogeneza. Éto podtverzhdaet nedavnee predpolozhenie o tom, chto PGC-1α ne iavliaetsia glavnym reguliatorom mitokhondrial'nogo biogeneza.