Mice Lacking Thyroid Hormone Receptor β Show Enhanced Apoptosis and Delayed Liver Commitment for Proliferation after Partial Hepatectomy

Abstract

BackgroundThe role of thyroid hormones and their receptors (TR) during liver regeneration after partial hepatectomy (PH) was studied using genetic and pharmacologic approaches. Roles in liver regeneration have been suggested for T3, but there is no clear evidence distinguishing the contribution of increased amounts of T3 from the modulation by unoccupied TRs.Methodology/Principal FindingsMice lacking TRα1/TRβ or TRβ alone fully regenerated liver mass after PH, but showed delayed commitment to the initial round of hepatocyte proliferation and transient but intense apoptosis at 48h post-PH, affecting ∼30% of the remaining hepatocytes. Pharmacologically induced hypothyroidism yielded similar results. Loss of TR activity was associated with enhanced nitrosative stress in the liver remnant, due to an increase in the activity of the nitric oxide synthase (NOS) 2 and 3, caused by a transient decrease in the concentration of asymmetric dimethylarginine (ADMA), a potent NOS inhibitor. This decrease in the ADMA levels was due to the presence of a higher activity of dimethylarginineaminohydrolase-1 (DDAH-1) in the regenerating liver of animals lacking TRα1/TRβ or TRβ. DDAH-1 expression and activity was paralleled by the activity of FXR, a transcription factor involved in liver regeneration and up-regulated in the absence of TR.Conclusions/SignificanceWe report that TRs are not required for liver regeneration; however, hypothyroid mice and TRβ– or TRα1/TRβ–deficient mice exhibit a delay in the restoration of liver mass, suggesting a specific role for TRβ in liver regeneration. Altered regenerative responses are related with a delay in the expression of cyclins D1 and E, and the occurrence of liver apoptosis in the absence of activated TRβ that can be prevented by administration of NOS inhibitors. Taken together, these results indicate that TRβ contributes significantly to the rapid initial round of hepatocyte proliferation following PH, and improves the survival of the regenerating liver at later times.

T3/TRs axis in hepatocellular carcinoma: new concepts for an old pair

“…These in vivo data are in agreement with those, in vitro, showing that Trβ, when not bound to T 3 , acts as a cell cycle inhibitor by inhibiting Cyclin D1 expression or repressing its induction by the oncogene Ha-Ras val12 (García-Silva et al 2004). However, they are in contrast with the finding that a significant delay in the restoration of liver mass post-PH occurs in mice lacking Trα1, Trβ1 or both receptors (López-Fontal et al 2010).…”

Vascular smooth muscle cell apoptosis is an early trigger for hypothyroid atherosclerosis

“…39 Due to obvious induction of aortic VSMC apoptosis in severe hypothyroidism, future work needs to pay attention on the development of aneurysmal dilation of such vessels. In addition to aortic VSMC apoptosis, hypothyroidism may cause apoptosis in other tissues, such as the brain, 40 liver, 41 and mammary tumour tissue. 42 One limitation for the present study was not to have obtained data on apoptosis in other tissues, especially cardiac and skeletal muscles.…”

Sulfotransferasegenes: Regulation by nuclear receptors in response to xeno/endo-biotics

“…By binding TH receptors TRα (NR1A1) and TRβ (NR1A2), T3 plays important roles in liver regeneration and overall energy expenditure (Brent, 2012; Lopez-Fontal et al, 2010). The pro-hormone 3,5,3′,5′-tetraiodothyronine (T4) is synthesized in and secreted from the thyroid gland.…”