Delineation of molecular pathways that regulate hepatic PCSK9 and LDL receptor expression during fasting in normolipidemic hamsters

Background: PCSK9 has emerged as a key regulator of serum LDL-C metabolism by promoting the degradation of hepatic LDL receptor (LDLR). In this study, we investigated the effect of fasting on serum PCSK9, LDL-C, and hepatic LDLR expression in hamsters and further delineated the molecular pathways involved in fasting-induced repression of PCSK9 transcription. Results: Fasting had insignificant effects on serum total cholesterol and HDL-C levels, but reduced LDL-C, triglyceride and insulin levels. The decrease in serum LDL-C was accompanied by marked reductions of hepatic PCSK9 mRNA and serum PCSK9 protein levels with concomitant increases of hepatic LDLR protein amounts. Fasting produced a profound impact on SREBP1 expression and its transactivating activity, while having modest effects on mRNA expressions of SREBP2 target genes in hamster liver. Although PPAR alpha mRNA levels in hamster liver were elevated by fasting, ligand-induced activation of PPARa with WY14643 compound in hamster primary hepatocytes did not affect PCSK9 mRNA or protein expressions. Further investigation on HNF1 alpha, a critical transactivator of PCSK9, revealed that fasting did not alter its mRNA expression, however, the protein abundance of HNF1 alpha in nuclear extracts of hamster liver was markedly reduced by prolonged fasting. Conclusion: Fasting lowered serum LDL-C in hamsters by increasing hepatic LDLR protein amounts via reductions of serum PCSK9 levels. Importantly, our results suggest that attenuation of SREBP1 transactivating activity owing to decreased insulin levels during fasting is primarily responsible for compromised PCSK9 gene transcription, which was further suppressed after prolonged fasting by a reduction of nuclear HNF1 alpha protein abundance. Published by Elsevier Ireland Ltd.