Thus, like mice with BDL-induced liver fibrosis, humans with NAFLD-related liver fibrosis acquire a pattern of hepatic deiodinase expression that is reminiscent of developmental organogenesis.
In summary, Hedgehog-regulated hepatic stromal cell responses that occur during adult liver repair shift the balance of local deiodinase expression to favor accumulation of biologically inert TH at the expense of biologically active TH.
Nevertheless, the available data in experimental animals indicate that Hedgehog-responsive myofibroblasts are key determinants of hepatic deiodinase expression and thereby, local TH activity during liver injury.
It is possible to speculate that despite reduced circulating thyroid hormone levels, thyroid hormone availability in specific adult brain regions may not exhibit as steep a decline through the modulation of local deiodinase expression and activity.
Taken together, our findings demonstrate that Hedgehog-responsive myofibroblasts are important regulators of hepatic deiodinase expression during liver injury and are partially responsible for the intrahepatic hypothyroidism that develops after BDL in mice.
Indeed, our work identified Hedgehog, an injury-induced signaling pathway, to be a key regulator of net hepatic deiodinase expression during liver injury.
The expression pattern of Iodothyronine deiodinase I (D1), which controls the conversion of T4 to T3 as well as the inactive metabolite rT3, was also assessed.
To further investigate this issue, we used αsmaCre-smoflx/flx mice to conditionally delete Smoothened (Smo), an obligate component of the canonical Hedgehog pathway, in myofibroblasts after BDL and compared deiodinase expression, hepatic TH levels, and hepatic expression of TH-regulated genes in mice with and without canonical signaling in HSCs.
Studies have now been carried out in Siberian hamsters to determine the functional significance of seasonal regulation of deiodinase gene expression.
Thus, injured liver tissue reacquires a deiodinase expression profile that is reminiscent of developing tissue in which there is limited exposure to TH.
