Docosahexaenoic acid-thyroid hormone combined protocol as a novel approach to metabolic stress disorders: Relation to mitochondrial adaptation via liver PGC-1α and sirtuin1 activation.

Docosahexaenoic acid (DHA) and 3,3',5-triiodothyronine (T3 ) combined protocol affords protection against liver injury via AMPK signaling supporting energy requirements. The aim of this work was to test the hypothesis that a DHA + T3 accomplish mitochondrial adaptation through downstream upregulation of PPAR-γ coactivator 1α (PGC-1α). Male Sprague-Dawley rats were given daily oral doses of 300 mg DHA/kg or saline (controls) for three consecutive days, followed by 0.05 mg T3 /kg (or hormone vehicle) ip at the fourth day, or single dose of 0.1 mg T3 /kg alone. Liver mRNA levels were assayed by qPCR, NAD+ /NADH ratios, hepatic proteins, histone 3 acetylation and serum T3 and β-hydroxybutyrate levels were determined by specific ELISA kits. Combined DHA + T3 protocol led to increased liver AMPK, PGC-1α, NRF-2, COX-IV, and β-ATP synthase mRNAs, with concomitant higher protein levels of COX-IV and NRF-2, 369% enhancement in the NAD+ /NADH ratio, 47% decrease in histone 3 acetylation and 162% increase in serum levels of β-hydroxybutyrate over control values. These changes were reproduced by the higher dose of T3 without major alterations by DHA or T3 alone. In conclusion, liver mitochondrial adaptation by DHA + T3 is associated with PGC-1α upregulation involving enhanced transcription of the coactivator, which may be contributed by PGC-1α deacetylation and phosphorylation by SIRT1 and AMPK activation, respectively. This contention is supported by NRF-2-dependent enhancement in COX-1 and β-ATP synthase induction with higher fatty acid oxidation resulting in a significant ketogenic response, which may represent a suitable strategy for hepatic steatosis with future clinical applications. © 2018 BioFactors, 45(2):271-278, 2019.