However, sirtuin 3 is an NAD+-dependent enzyme, and either the ab

However, sirtuin 3 is an NAD+-dependent enzyme, and either the abundance or the availability of NAD+ may have been changed by the absence of Hint2 in mitochondria. Alternatively, Hint2 may have influenced the acetyl-transferase processes in mitochondria. A change in the acetylation status of selected proteins could explain several other Hint2−/− phenotypic changes. Hepatic steatosis may

be related to an impaired, hyperacetylated Hadhsc protein, since there is an association between Hadhsc deficiency and liver steatosis.23 Moreover, mitochondrial hyperacetylation of multiple proteins due to sirtuin 3 deficiency accelerates the development of metabolic syndrome.24 The impaired thermoregulation Hint2−/− mice could also be explained by an effect on acetylation, Fulvestrant ic50 since BAT expresses both sirtuin

325 and Hint2 (Fig. 5) and BAT proteins are regulated by acetylation during fasting.26 The reduced respiration in Hint2−/− and silenced HINT2-HepG2 mitochondria could be a primary defect due to the reduced linked complex II-III electron transport and coenzyme Q levels, which in turn could explain the increased reactive oxygen species production.27 Certain components of the electron transport chain are regulated by acetylation,28 which may have been altered in Hint2−/− mitochondria. The cause of the reduced coenzyme Q was not clarified, but a down-regulation of biosynthetic genes at the transcriptional level could be excluded. The appearance of large deformed Hint2−/− mitochondria was check details an age-dependent feature and different from the structural mTOR inhibitor alterations with cristolysis

described in respiratory chain disorders, where fusion and fission were perturbed.29 Because Hint2 was detected solely in the exocrine pancreatic fraction, the two-fold increase in interprandial insulin levels in Hint2−/− mice remains unexplained but was not indicative of insulin resistance (Supporting Fig. 3B). A steatosis-mediated reduction of hepatic insulin clearance was unlikely because insulin was higher in Hint2−/− even after Hint2+/+ livers showed signs of steatosis. The apparent discrepancy between the increase in interprandial insulin and the decrease in glucose-stimulated insulin secretion, which could account for the lower glucose tolerance in Hint2−/− mice, was also not resolved in our experiments, but it is clear that deletion of Hint2 has affected basal and glucose-stimulated insulin secretion in different ways. The up-regulation of leptin mRNA expression in Hint2−/− WAT was possibly secondary to the higher basal insulin and glucocorticoid concentrations.30, 31 The failure of Hint2−/− mice to mount an appropriate counter-regulatory response to hypoglycemia is also not explained, but an impaired hepatic GDH enzyme combined with a lower expression of Pck1 after insulin (Fig. 4B and Supporting Fig. 3A) may have contributed to the poor ITT recovery phase.

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