Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that plays a key role in hepatocyte differentiation and the maintenance of hepatic function, but its role in hepatocarcinogenesis has yet to be examined. Here, we report evidence of a suppressor role for HNF4α in liver cancer. HNF4α expression was progressively decreased in the diethylinitrosamine-induced rat model of liver carcinogenesis. In human liver tissues, HNF4α expression was decreased in cirrhotic tissue and further decreased in hepatocarcinoma relative to healthy tissue. Notably, an inverse correlation existed with epithelial-mesenchymal transition (EMT). Enforced expression of HNF4α attenuated hepatocyte EMT during hepatocarcinogenesis, alleviated hepatic fibrosis, and blocked hepatocellular carcinoma (HCC) occurrence. In parallel, stem cell marker gene expression was inhibited along with cancer stem/progenitor cell generation. Further, enforced expression of HNF4α inhibited activation of β-catenin, which is closely associated with EMT and hepatocarcinogenesis. Taken together, our results suggest that the inhibitory effect of HNF4α on HCC development might be attributed to suppression of hepatocyte EMT and cancer stem cell generation through an inhibition of β-catenin signaling pathways. More generally, our findings broaden knowledge on the biological significance of HNF4α in HCC development, and they imply novel strategies for HCC prevention through the manipulation of differentiation-determining transcription factors in various types of carcinomas.

Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a nuclear receptor that plays a pivotal role in obesity and diabetes. PPAR␥ has two isoforms, PPAR␥1 and PPAR␥2. We investigated the functional differences between PPAR␥1 and PPAR␥2 by selectively disrupting PPAR␥2 in mice. In contrast to the embryonic lethality of PPAR␥-deficient mice, PPAR␥2 ؊/؊ mice survived. Although normal development was identified in other tissues we examined, PPAR␥2 ؊/؊ mice exhibited an overall reduction in white adipose tissue, less lipid accumulation, and decreased expression of adipogenic genes in adipose tissue. In addition, insulin sensitivity was impaired in male PPAR␥2 ؊/؊ mice, with dramatically decreased expression of insulin receptor substrate 1 and glucose transporter 4 in the skeletal muscle, but thiazolidinediones were able to normalize this insulin resistance. Consistent with in vivo data, PPAR␥2 ؊/؊ mouse embryonic fibroblasts showed a dramatically reduced capacity for adipogenesis in vitro compared with wildtype mouse embryonic fibroblasts. Taken together, our data demonstrate that PPAR␥2 deficiency impairs the development of adipose tissue and insulin sensitivity. PPAR␥2 ؊/؊ mice may provide a tool to study the role of PPAR␥2 in obesity and diabetes.adipogenesis ͉ obesity ͉ diabetes