Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

Abstract

Objectives Although the hepatomitogenic activity of triiodothyronine (T3) is well established, the wide range of harmful effects exerted by this hormone precludes its use in liver regenerative therapy. Selective agonists of the beta isoform of thyroid hormone receptor (TRβ) do not exhibit T3‐induced cardiotoxicity and show a good safety profile in patients with NASH. The aim of this study was to investigate whether two novel TRβ agonists, the prodrug TG68 and the active compound IS25 could stimulate hepatocyte proliferation without T3/TRα‐dependent side effects. Methods Rats were treated with three different doses (12.5, 25 and 50 μg/100 g body weight) for one week. Hepatocyte proliferation, liver injury and serum biochemical parameters were measured by immunohistochemistry, qRT‐PCR and Western blot. Results Both drugs increased hepatocyte proliferation as assessed by bromodeoxyuridine incorporation (from 14% to 28% vs 5% of controls) and mitotic activity. Enhanced proliferation occurred in the absence of significant signs of liver injury as shown by lack of increased serum transaminase levels or of apoptosis. No cardiac or renal hypertrophy typically associated with treatment with T3 was observed. Importantly, no proliferation of pancreatic acinar cells, such as that seen after administration of T3 or the TRβ agonist GC1 was detected following either TG68 or IS25, demonstrating the hepato‐specificity of these novel TRβ agonists. Conclusions The present study shows that TG68 and IS25 induce massive hepatocyte proliferation without overt toxicity. Hence, these agents may have a significant clinical application for regenerative therapies in liver transplantation or other surgical settings.

TG68, a Novel Thyroid Hormone Receptor-β Agonist for the Treatment of NAFLD

“…As already observed in previous studies [ 22 , 23 ], the administration of TG68 in HFD-fed mice lowered the serum levels of ALT and AST, revealing that, in addition to revert a condition of simple steatosis, it may also efficiently ameliorate the background of cell death typical of NASH. Furthermore, TG68 can also significantly reduce serum TAGs.…”

“…Both IS25 and TG68, when tested for cytotoxicity and ADME-Tox/off-target liability in vitro, revealed a convincing lack of toxicity and the capacity to reduce total lipid accumulation into lipid droplets with an effect comparable, or even higher, than equimolar doses of T3 [ 22 ]. Further in vivo studies showed that both compounds were able to increase hepatocyte proliferation, in a way quite similar to the thyroid hormone T3, but in the absence of liver damage, cardiotoxicity, and renal hypertrophy [ 23 ], demonstrating a marked hepato-specificity. Based on these encouraging preliminary results, we decided to investigate prodrug TG68 in a NASH mouse model in order to explore its potential to treat this liver syndrome.…”

Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

“…Since its initial development, many analogs of GC-1 have been designed and tested for functionality, selectivity, and permeability [ 38 , 39 ]. In particular, IS25 and TG68 ( Figure 1 ) showed encouraging off-target and ADME-Tox profiles both in vitro and in vivo [ 40 , 41 ], facilitating liver proliferation and alleviating lipid metabolism disorders, without exhibiting T 3 -induced cardiotoxicity [ 42 ].…”

Selective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders

“…Therefore, TRβ-selective thyromimetics devoid of relevant side effects might find a possible use in regenerative medicine ( 83 , 96 ). Even though still at a preliminary level, ongoing studies have revealed that in F344 rats a sub-chronic treatment with the two novel TRβ-agonists, namely IS25 and TG68, induced hepatocyte proliferation in the absence of any sign of hepatic toxicity and cardiac hypertrophy ( 75 ). Notably, hepatocyte proliferation appears to be associated with activation of TR-target genes, such as Dio1 and Spot14, suggesting that the mitogenic effect of these drugs may be due to binding and activation of TRβ.…”

“…Notably, hepatocyte proliferation appears to be associated with activation of TR-target genes, such as Dio1 and Spot14, suggesting that the mitogenic effect of these drugs may be due to binding and activation of TRβ. Importantly, the liver proliferative response induced by the two TRβ agonists was not associated with liver damage, as assessed by biochemical determination of serum transaminases and by immunostaining for Caspase-3, but it was the result of a direct effect of these drugs enabling quiescent hepatocytes to re-entry into the cell cycle ( 75 ). Hence these newly developed agents may have a significant clinical application for hepatic regenerative therapies or other surgical procedures.…”