Thyroid Hormone-Induced Cytosol-to-Nuclear Translocation of Rat Liver Nrf2 Is Dependent on Kupffer Cell Functioning

Abstract

L-3,3′,5-triiodothyronine (T3) administration upregulates nuclear factor-E2-related factor 2 (Nrf2) in rat liver, which is redox-sensitive transcription factor mediating cytoprotection. In this work, we studied the role of Kupffer cell respiratory burst activity, a process related to reactive oxygen species generation and liver homeostasis, in Nrf2 activation using the macrophage inactivator gadolinium chloride (GdCl3; 10 mg/kg i.v. 72 h before T3 [0.1 mg/kg i.p.]) or NADPH oxidase inhibitor apocynin (1.5 mmol/L added to the drinking water for 7 days before T3), and determinations were performed 2 h after T3. T3 increased nuclear/cytosolic Nrf2 content ratio and levels of heme oxygenase 1 (HO-1), catalytic subunit of glutamate cysteine ligase, and thioredoxin (Western blot) over control values, proteins whose gene transcription is induced by Nrf2. These changes were suppressed by GdCl3 treatment prior to T3, an agent-eliciting Kupffer-cell depletion, inhibition of colloidal carbon phagocytosis, and the associated respiratory burst activity, with enhancement in nuclear inhibitor of Nrf2 kelch-like ECH-associated protein 1 (Keap1)/Nrf2 content ratios suggesting Nrf2 degradation. Under these conditions, T3-induced tumor necrosis factor-α (TNF-α) response was eliminated by previous GdCl3 administration. Similar to GdCl3, apocynin given before T3 significantly reduced liver Nrf2 activation and HO-1 expression, a NADPH oxidase inhibitor eliciting abolishment of colloidal carbon-induced respiratory burst activity without altering carbon phagocytosis. It is concluded that Kupffer cell functioning is essential for upregulation of liver Nrf2-signaling pathway by T3. This contention is supported by suppression of the respiratory burst activity of Kupffer cells and the associated reactive oxygen species production by GdCl3 or apocynin given prior to T3, thus hindering Nrf2 activation.

Roles of Thyroid Hormone-Associated microRNAs Affecting Oxidative Stress in Human Hepatocellular Carcinoma

“…Several animal studies have provided evidence to support a positive association of thyroid hormone with Nrf2, a key redox-sensitive transcription factor of antioxidant genes, in the liver. Thyroid hormone not only upregulates Nrf2, but also promotes antioxidant gene expression, since Nrf2 translocates from the cytosol to nucleus, mediating hepatic cytoprotection [188][189][190][191].…”

Thyroid hormone in the frontier of cell protection, survival and functional recovery

“…63) and Kupffer cell-dependent processes (Ref. 64), with concomitant antioxidant protein expression (Ref. 65) (Fig.…”

Metabolic Basis for Thyroid Hormone Liver Preconditioning: Upregulation of AMP-Activated Protein Kinase Signaling

“…These responses and the promotion of hepatocyte and Kupffer-cell proliferation represent hormetic effects reestablishing redox homeostasis, promoting cell survival, and protecting the liver against ischemia-reperfusion injury [ 51 ]. T 3 liver preconditioning also involves the activation of the Nrf2-Keap1 defense pathway [ 52 , 53 ], upregulating antioxidant proteins, phase-2 detoxifying enzymes, and multidrug resistance proteins, members of the ATP binding cassette (ABC) superfamily of transporters ( Figure 3(B) ) [ 24 , 54 ]. In agreement with T 3 -induced liver preconditioning, T 3 or L-thyroxin afford preconditioning against IR injury in the heart, in association with activation of protein kinase C [ 55 ] and attenuation of p38 and c-Jun-N-terminal kinase activation [ 56 ], and in the kidney, in association with heme oxygenase-1 upregulation [ 57 ].…”