Abrogation of Hepatic TRβ Action Protects the Liver from Acute Liver Injury

Overdose of acetaminophen (APAP) is a well-known trigger for acute liver failure. Even if the underlying mechanisms of ALF are not yet fully understood, it is well known that triiodothyronine (T3) positively favors hepatocyte proliferation via thyroid hormone receptor β (TRβ) signaling. We observed that abrogation of hepatic TRβ action attenuates APAP-induced acute liver injury and that a crucial time-specific modulation of ALF through TH exists whereas T3 improved hepatocyte proliferation during liver regeneration.

ALF was induced via i.p. injection of 300 mg/kg body weight of APAP (or solvent control) in male C57BL/6J mice w/o hepatocyte specific TRβ knockout. 1- 24h post APAP intoxication, liver function test, liver histology, proliferation and hepatic T3- and APAP-responsive markers were evaluated.

APAP intoxication in hepatocyte-specific TRβ deletion mice (hepTRβKO) resulted in absence of pericentral hepatocellular necrosis and absence of elevated serum transaminases 24 hours post APAP intoxication as compared to WT mice. Interestingly, 12 hours after APAP application injured hepatocytes surrounding central veins could be observed in hepTRβKO mice.

We hypothesize a hepatocyte-intrinsic detrimental TH effect in disease development, whereas TH action during liver regeneration is beneficial. These findings harbor great translational potential for novel therapeutic strategies, e.g. to antagonize or agonize local TH action, depending on the disease status of patients suffering from ALF. It is of high clinical relevance if one could support the so far only therapeutic option NAC in the treatment of APAP-induced ALF, preferably with a prolonged therapeutic window.

 

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Publication History

Article published online:
20 January 2025