Però c’è da dire che, l’aumento dei livelli di FGF21 e la riduzione di ApoCIII dati dal trattamento,
potrebbero avere un impatto positivo sulla riduzione dell’insulinoresistenza: infatti, si è visto che la
somministrazione di un analogo di FGF21 migliorava l’insulinoresistenza e il metabolismo
glucidico
256e che ridurre ApoCIII per contro aumentava la sensibilità insulinica
257Per quanto riguarda invece il profilo lipoproteico, il pemafibrato e gli agonisti del PPAR α, sono ritenuti in grado di aumentare l’uptake epatico di NEFA e la loro betaossidazione, e di ridurre l’aumentata lipogenesi e la produzione di VLDL225.
È stato dimostrato anche che il pemafibrato aumenta, in epatociti umani, murini e in fegati di ratto258,259,
l’espressione di geni per la betaossidazione ed il contenuto epatico di Tg259, e che esso è in grado di inibire
l’espressione del mRNA di NPC1L1, di pari passo con un aumento dell’escrezione fecale di colesterolo in topi knock-out per il recettore delle LDL260.
I fibrati, sembrano anche ridurre l’assorbimento intestinale del colesterolo probabilmente tramite una riduzione di NPC1L1, Microsomal Transfer Protein e dell’mRNA di ApoB261,262.
I livelli di ApoB48, principale componente dei chilomicroni, ridotti dal trattamento con pemafibrato, presumibilmente riflettono la riduzione nella produzione di chilomicroni da parte dell’intestino e/o un aumentato catabolismo.
Inoltre, gli agonisti del PPAR α hanno mostrato di incrementare l’espressione di LPL e di inibire quella di ApoCIII, la quale sopprime l’attività lipolitica225. Il pemafibrato riduce in maniera marcata i livelli di ApoCIII
ed è proprio attraverso questi meccanismi, cioè sopprimendo la produzione ed aumentando il catabolismo delle lipoproteine ricche in Tg, che riesce ad incrementare i livelli di HDL-c ed a ridurre i livelli di LDL piccole e dense, che hanno il massimo potere aterogenico263.
Lo studio di Araki non era finalizzato a dimostrare l’efficacia del pemafibrato nel ridurre gli eventi cardiovascolari, tuttavia, i risultati degli altri studi, le evidenze sul suo ruolo e su quello degli altri agonisti del PPAR α nel modulare l’assetto lipoproteico e migliorare la dislipidemia, lasciano ben sperare che questi farmaci possano agire in tal senso, migliorando nettamente l’outcome dei pazienti diabetici.
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