YAP regulates the liver size during the fasting-refeeding transition in mice.

Liver is the central hub regulating energy metabolism during feeding-fasting transition. Evidence suggests that fasting and refeeding induce dynamic changes in liver size, but the underlying mechanisms remain unclear. Yes-associated protein (YAP) is a key regulator of organ size. This study aims to explore the role of YAP in fasting- and refeeding-induced changes in liver size. Here, fasting significantly reduced liver size, which was recovered to the normal level after refeeding. Moreover, hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting. Conversely, refeeding promoted hepatocyte enlargement and proliferation compared to fasted state. Mechanistically, fasting or refeeding regulated the expression of YAP and its downstream targets, as well as the proliferation-related protein cyclin D1 (CCND1). Furthermore, fasting significantly reduced the liver size in AAV-control mice, which was mitigated in AAV Yap (5SA) mice. Yap overexpression also prevented the effect of fasting on hepatocyte size and proliferation. Besides, the recovery of liver size after refeeding was delayed in AAV Yap shRNA mice. Yap knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation. In summary, this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition, which provides new evidence for YAP in regulating liver size under energy stress.

Mapping hepatocyte size in vivo using temporal diffusion spectroscopy MRI.

PURPOSE: The goal of this study is to implement a noninvasive method for in vivo mapping of hepatocyte size. This method will have a broad range of clinical and preclinical applications, as pathological changes in hepatocyte sizes are relevant for the accurate diagnosis and assessments of treatment response of liver diseases. METHODS: Building on the concepts of temporal diffusion spectroscopy in MRI, a clinically feasible imaging protocol named IMPULSED (Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion) has been developed, which is able to report measurements of cell sizes noninvasively. This protocol acquires a selected set of diffusion imaging data and fits them to a model of water compartments in tissues to derive robust estimates of the cellular structures that restrict free diffusion. Here, we adapt and further develop this approach to measure hepatocyte sizes in vivo. We validated IMPULSED in livers of mice and rats and implemented it to image healthy human subjects using a clinical 3T MRI scanner. RESULTS: The IMPULSED-derived mean hepatocyte sizes for rats and mice are about 15-20 µm and agree well with histological findings. Maps of mean hepatocyte size for humans can be achieved in less than 15 minutes, a clinically feasible scan time. CONCLUSION: Our results suggest that this method has potential to overcome major limitations of liver biopsy and provide noninvasive mapping of hepatocyte sizes in clinical applications.