Combined docosahexaenoic acid and thyroid hormone supplementation as a protocol supporting energy supply to precondition and afford protection against metabolic stress situations

Abstract

Liver preconditioning (PC) refers to the development of an enhanced tolerance to injuring stimuli. For example, the protection from ischemia–reperfusion (IR) in the liver that is obtained by previous maneuvers triggering beneficial molecular and functional changes. Recently, we have assessed the PC effects of thyroid hormone (T3; single dose of 0.1 mg/kg) and n‐3 long‐chain polyunsaturated fatty acids (n‐3 LCPUFAs; daily doses of 450 mg/kg for 7 days) that abrogate IR injury to the liver. This feature is also achieved by a combined T3 and the n‐3 LCPUFA docosahexaenoic acid (DHA) using a reduced period of supplementation of the FA (daily doses of 300 mg/kg for 3 days) and half of the T3 dosage (0.05 mg/kg). T3‐dependent protective mechanisms include (i) the reactive oxygen species (ROS)‐dependent activation of transcription factors nuclear factor‐κB (NF‐κB), AP‐1, signal transducer and activator of transcription 3, and nuclear factor erythroid‐2‐related factor 2 (Nrf2) upregulating the expression of protective proteins. (ii) ROS‐induced endoplasmic reticulum stress affording proper protein folding. (iii) The autophagy response to produce FAs for oxidation and ATP supply and amino acids for protein synthesis. (iv) Downregulation of inflammasome nucleotide‐bonding oligomerization domain leucine‐rich repeat containing family pyrin containing 3 and interleukin‐1β expression to prevent inflammation. N‐3 LCPUFAs induce antioxidant responses due to Nrf2 upregulation, with inflammation resolution being related to production of oxidation products and NF‐κB downregulation. Energy supply to achieve liver PC is met by the combined DHA plus T3 protocol through upregulation of AMPK coupled to peroxisome proliferator‐activated receptor‐γ coactivator 1α signaling. In conclusion, DHA plus T3 coadministration favors hepatic bioenergetics and lipid homeostasis that is of crucial importance in acute and clinical conditions such as IR, which may be extended to long‐term or chronic situations including steatosis in obesity and diabetes. © 2019 IUBMB Life, 71(9):1211–1220, 2019

Impact of the Co-Administration of N-3 Fatty Acids and Olive Oil Components in Preclinical Nonalcoholic Fatty Liver Disease Models: A Mechanistic View

“…EPA is a precursor of DHA [41], which contributes to the enhancement in liver DHA availability [33]. Compared with EPA, DHA exhibits a greater chemical reactivity [7] associated with the formation of active derivatives ( Figure 2) [42][43][44] and affords more beneficial effects than EPA [45,46]. DHA binding to peroxisome proliferator-activated receptor-α (PPAR-α) leads to PPAR-α activation with enhanced binding capacity to DNA, promoting the expression of genes encoding for proteins involved in different aspects of FA metabolism [47].…”

“…This may reflect that the interaction of the underlying mechanisms (Figures 2 and 3) is inadequately exerted in relation to either the intracellular levels of the agents that are actually achieved or differences in their potency to trigger significant responses. In the case of the supplementation with DHA and HT, however, these factors seem to be overcome, since (i) liver DHA levels are higher than those of EPA under normal conditions [9,37,38,40]; (ii) DHA administration to control and HFD-fed mice reaches higher than basal DHA levels in the liver [37]; (iii) DHA is more reactive [7] and beneficial than EPA [45,46,81]; and (iv) the in vivo HT supplementation represents a greater HT dosage (5 mg/kg/day) [38][39][40] than that given as EVOO (Figure 3), thus inhibiting steatosis development ( Figure 1D). Accordingly, under conditions of combined DHA and HT administration, an additive antisteatotic effect is attained, since the hepatic steatosis score induced by HFD is diminished by 64%, 38%, and 100% by DHA, HT, and DHA plus HT supplementation, respectively [56].…”

“…Furthermore, NAFLD is a multifactorial illness that includes complex metabolic changes, not only in the liver but also in adipose tissue and muscle, which suggest that monotherapies are unlikely to elicit successful responses [4]. In view of these considerations, new therapeutic approaches were evaluated using the combination of bioactive compounds, a strategy that is characterized by (i) the use of lower doses of compounds than monotherapies with shorter supplementation periods to minimize possible side effects; and (ii) the involvement of compounds with protective effects that are exerted through different or similar mechanisms of action, thus allowing synergistic or additive actions and a more efficient control of the damaging effects [4,7]. For example, (i) preservation of liver tissue regeneration post-hepatectomy can be obtained by a L-3,3 ,5-triiodothyronine (T 3 ) plus methylprednisolone treatment [8]; (ii) high-fat diet (HFD)-induced liver steatosis can be diminished by n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) and extra virgin olive oil (EVOO) [9]; (iii) combined T 3 and fish oil supplementation suppresses ischemia-reperfusion inflammatory liver injury [10]; whereas (iv) resveratrol and enalapril improved glucose and lipid profiles by decreasing lipogenic gene expression [11].…”

Docosahexaenoic acid and hydroxytyrosol co‐administration fully prevents liver steatosis and related parameters in mice subjected to high‐fat diet: A molecular approach

“…Development of a drastic oxidative stress by HFD underlying PPAR-α down-regulation may be ascribed to an oxidative deterioration of n-3 LCPUFAs inducing their depletion, 9,10,16,43 as also observed in the liver of NAFLD patients, 38,39 a property related to their high susceptibility to oxidation linked to the elevated degree of unsaturation. 44 N-3 LCPUFA depletion involving low PPAR-α activity is associated with diminution in liver Δ5and Δ6-desaturase activity secondary to insulin resistance observed in HFD fed animals 16 and in obese NAFLD patients, 45 considering that insulin induces the expression of both desaturases. 46 In the latter case, loss of desaturase activity may be contributed by inadequate intake of the n-3 LCPUFA precursor α-linolenic acid (C18:3n-3; ALA) and/or higher consumption of desaturase inhibitors including trans FAs.…”

“…12,69 4 | CONCLUDING REMARKS Data presented show that liver steatosis induced by HFD in mice is fully prevented by the co-administration of DHA and HT, in comparison with other combined protocols such as EPA plus HT that only attains fatty liver attenuation. 10,11 In this respect, DHA constitutes a crucial protective n-3 LCPUFA due to the attainment of higher than normal levels in the liver upon supplementation 16 and to its greater chemical reactivity 44 promoting the formation of active derivatives, 12,15,19 which afford more beneficial effects compared to EPA. 13,14 Thus, the higher effectiveness of the anti-steatotic action of the DHA plus HT protocol is primarily linked to suppression of hepatic oxidative stress, with concomitant repletion of n-3 LCPUFAs and normalization the lipogenic/FA oxidation pattern of the liver (SREBP-1c/PPAR-α ratio) that are drastically disturbed by HFD, with the underlying mechanisms showing additive effects exerted by the individual natural products.…”