Thiazolidinediones inhibit liver regeneration

The liver responds to injury with regulated tissue regeneration. Studies using the partial hepatectomy model have identified many signals activated during such regeneration. Nevertheless, an integrated understanding of the mechanisms that regulate liver regeneration remains elusive. New insight was recently provided by studies reporting the importance of hepatocellular fat accumulation during liver regeneration; however, the mechanisms that regulate hepatic adipogenesis during regeneration have not been identified. One possibility is that the peroxisome proliferator activated receptor (PPAR)‐γ, which influences lipid metabolism, regulates hepatic adipogenesis during liver regeneration. Therefore, we investigated the effect of PPARγ‐activating thiazolidinediones on liver regeneration. In these studies, mice were treated with vehicle, pioglitazone, or rosiglitazone, subjected to partial hepatectomy, allowed to recover, then sacrificed for analysis of hepatic regeneration. The drug dosing regimen used in these studies (10 mg/kg gavage bid) is well tolerated and within the range typically used to elicit PPARγ‐dependent changes in insulin sensitivity in mouse models of diabetes. Our results showed that these thiazolidinediones inhibited hepatic fat accumulation, cellular proliferation, and cyclin expression during liver regeneration with potency corresponding to their efficacy of PPARγ activation. These results suggest that PPARγ is an important regulator of hepatic regeneration and implicate impaired hepatic regeneration as a candidate mechanistic explanation for the hepatotoxicity associated with clinical thiazolidinedione use. These studies were supported by grants from NIH and March of Dimes.