Premium
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
Author(s) -
Vargas Romina,
Riquelme Bárbara,
Fernández Javier,
Álvarez Daniela,
Pérez Ignacio F.,
Cornejo Pamela,
Fernández Virginia,
Videla Luis A.
Publication year - 2018
Publication title -
biofactors
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.204
H-Index - 94
eISSN - 1872-8081
pISSN - 0951-6433
DOI - 10.1002/biof.1483
Subject(s) - downregulation and upregulation , endocrinology , ampk , docosahexaenoic acid , medicine , nad+ kinase , beta oxidation , chemistry , biology , protein kinase a , biochemistry , metabolism , kinase , fatty acid , enzyme , polyunsaturated fatty acid , gene
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‐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 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 β‐hydroxybutyrate levels were determined by specific ELISA kits. Combined DHA + T 3 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 T 3 without major alterations by DHA or T 3 alone. In conclusion, liver mitochondrial adaptation by DHA + T 3 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