Upregulation of rat liver PPARα‐FGF21 signaling by a docosahexaenoic acid and thyroid hormone combined protocol

Abstract

Prevention of ischemia-reperfusion liver injury is achieved by a combined omega-3 and thyroid hormone (T ) protocol, which may involve peroxisome-proliferator activated receptor-α (PPAR-α)-fibroblast growth factor 21 (FGF21) signaling supporting energy requirements. Combined docosahexaenoic acid (DHA; daily doses of 300 mg/kg for 3 days) plus 0.05 mg T /kg given to fed rats elicited higher hepatic DHA contents and serum T levels, increased PPAR-α mRNA and its DNA binding, with higher mRNA expression of the PPAR-α target genes for carnitine-palmitoyl transferase 1α, acyl-CoA oxidase, and 3-hydroxyl-3-methylglutaryl-CoA synthase 2, effects that were mimicked by 0.1 mg T /kg given alone or by the PPAR-α agonist WY-14632. Under these conditions, the mRNA expression of retinoic X receptor-α (RXR-α) is also increased, with concomitant elevation of the hepatic mRNA and protein FGF21 levels and those of serum FGF21. It is concluded that PPAR-α-FGF21 induction by DHA combined with T may involve ligand activation of PPAR-α by DHA and enhanced expression of PPAR-α by T , with consequent upregulation of the FGF21 that is controlled by PPAR-α. Considering the beneficial effects of PPAR-α-FGF21 signaling on carbohydrate and lipid metabolism, further investigations are required to clarify its potential therapeutic applications in human metabolic disorders. © 2016 BioFactors, 42(6):638-646, 2016.

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

“…5) promotes lipolysis in adipose tissue and the FAs released are used by the liver for energy production and ketogenesis [51]. In agreement, DHA + T 3 supplementation enhanced FGF21 levels in serum and hepatic expression of HMGCoAS2 for ketone body synthesis [30], which favors hepatic lipid homeostasis that is of importance in metabolic disorders or repair under liver injury conditions such as hepatic steatosis in obesity or ischemia-reperfusion inflammatory injury [2].…”

“…Combined DHA and T 3 administration, resulting in elevations in the serum levels of T 3 in association with a calorigenic response ( Fig. 1) and in the hepatic content of DHA [30], also upregulated liver PGC-1α gene expression in relation to PPARα-FGF21-AMPK signaling, an effect that is not observed with the separate treatments. Under these conditions, PPAR-α activation is triggered by DHA acting as a natural ligand for PPARα inducing a conformational change in the ligand-binding domain that favors recruitment of coactivators and the heterodimerization with RXR [33,34], whereas T 3 leads to the induction of the PPAR-α [30] (Fig.…”

“…These findings are in agreement with studies using more drastic conditions, namely, hypothyroid rats given 0.5 mg T 3 /kg and 6 h exposure enhancing liver PGC-1α mRNA expression [27] and euthyroid rats subjected to 0.4 mg T 3 /kg for five consecutive days inducing PGC-1α protein levels in muscle and liver, but not in heart [28]. The administration of a single dose of T 3 triggering liver PGC-1α upregulation may involve the PPAR-α-FGF21-AMPK signaling cascade, considering that (a) PPAR-α is required for induction of FGF21 by T 3 , in addition to that of thyroid hormone receptor β (TRβ) and retinoic X receptor (RXR) needed for T 3 functioning [29], a contention that is supported by the concomitant T 3 -dependent induction of PPAR-α target genes including carnitine palmitoyltransferase-1α (CPT-1α), acyl-CoA oxidase (ACOX) and hydroxymethylglutaryl-CoA synthese-2 (HMGCoAS2) [30,31]; (b) T 3 -induced FGF21 upregulation enhances AMPK activity by phosphorylation via activation of upstream kinases [17,28], a process that is assisted by the parallel induction of the scaffold proteins β-Klotho, FGF21 receptor substrate 2α (FRS2α) and sestrin2 [32]; and (c) T 3induced AMPK-dependent cyclic-AMP response element binding protein (CREB) phosphorylation [18,29], which in turn triggers PGC-1α mRNA expression [26], an effect that can be directly achieved by T 3 [18]. In general terms, upregulation of PPARα-FGF21-AMPK signaling attains induction of PPAR-α target genes through interaction of PPAR-α with PGC-1α with the formation of complexes with other coactivators and enzymes to accomplish full transcriptional activation.…”

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

“…In this respect, the interaction of the DNA binding domain of PPAR‐α with DHA induces conformational changes that enhance its transcriptional potential , whereas T 3 directly increases the hepatic mRNA levels and the DNA binding capacity of PPAR‐α . The latter mechanism is related to the genomic action of T 3 that is characterized by (i) the concomitant induction of TR and RXR‐α needed for full activation of gene transcription; (ii) the higher mRNA expression of the typical PPAR‐α target genes CPT‐1α , ACOX , and 3‐hydroxyl‐3‐methylglutarylCoA synthase 2 (HMGCoAS2) that is mimicked by the PPAR‐α agonist WY‐14632 ; and (iii) the PPAR‐α‐dependent upregulation of hepatic expression of FGF21 , as evidenced by the lack of T 3 ‐induced FGF21 expression reported in the PPAR‐α knockout mouse . FGF21 is a hepatokine exhibiting autocrine and endocrine effects that are related to energy homeostasis by modulation of glucose and lipid metabolism .…”

Thyroid Hormone-Induced Expression of the Hepatic Scaffold Proteins Sestrin2, β-Klotho, and FRS2α in Relation to FGF21-AMPK Signaling

“…β-Klotho and FRS2 induction favours the operation of the FGF21-FGFR1-β-Klotho complex as evidenced by the enhancement in ERK1/2 phosphorylation, whereas that of Ses-trin2 recruits LKB1 to achieved AMPK activation, thus supporting a higher energy expenditure condition that may be desirable in some metabolic disorders conditioning action of T 3 against hepatic ischemia-reperfusion injury, which may power the operation of antioxidant, antiapoptotic, anti-inflammatory, and cell proliferation responses that increase the homeostatic potential of the liver [9]. AMPK Thr phosphorylation is a complex process that can be attained by FGF21 signaling [10], which, in turn, is dependent upon induction by peroxisomeproliferator activated receptor α (PPARα) [11], metabolic regulators that are upregulated by T 3 administration in a time-and dosedependent process [12,13]. According to these considerations, the aim of this study was to assess the influence of T 3 on the expression of liver Sestrin2, β-Klotho, and FGF receptor substrate 2α (FRS2α), scaffold components that are essential for full operation of the FGF21-AMPK signaling cascade in the intact cell [14,15].…”