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 (T-3) 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 + T-3 accomplish mitochondrial adaptation through downstream upregulation of PPAR-gamma coactivator 1 alpha (PGC-1 alpha). 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 T-3/kg (or hormone vehicle) ip at the fourth day, or single dose of 0.1 mg T-3/kg alone. Liver mRNA levels were assayed by qPCR, NAD(+)/NADH ratios, hepatic proteins, histone 3 acetylation and serum T-3 and beta-hydroxybutyrate levels were determined by specific ELISA kits. Combined DHA + T-3 protocol led to increased liver AMPK, PGC-1 alpha, NRF-2, COX-IV, and beta-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 beta-hydroxybutyrate over control values. These changes were reproduced by the higher dose of T-3 without major alterations by DHA or T-3 alone. In conclusion, liver mitochondrial adaptation by DHA + T-3 is associated with PGC-1 alpha upregulation involving enhanced transcription of the coactivator, which may be contributed by PGC-1 alpha deacetylation and phosphorylation by SIRT1 and AMPK activation, respectively. This contention is supported by NRF-2-dependent enhancement in COX-1 and beta-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. (c) 2018 BioFactors, 45(2):271-278, 2019