Chang Kyung (Joanna) Kim, MD, PhD

Irwin M. Arias, MD Postdoctoral Research Fellowship Award
$25,000 over one year

University of Pittsburgh Medical Center

The Role of Hypoxia in WNT/β-catenin-Mediated Regulation of Liver Zonation and Regeneration

Mentor: Satdarshan (Paul) Monga, MD

The liver is a vital organ that carries out essential functions, including metabolism and detoxification. To maximize the functional efficiency, the liver is organized into three zones defined by their location along the porto-central blood flow and specific metabolic functions, a phenomenon known as liver zonation (LZ). Zone 1 is closest to the portal vein and receives the most nutrients and oxygen; Zone 2 is the intermediate area; and Zone 3 is closest to the central vein and receives less oxygenated blood. LZ is disrupted in many liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and cirrhosis, thus impairing optimal liver functions and resulting in serious complications at advanced stage. While the disruption could be consequences of injuries, it is unclear whether the altered LZ also plays a role in worsening the disease processes. We have a special interest in elucidating the role of WNT/β-catenin signaling in healthy and diseased livers and have previously showed that WNT/β-catenin signaling is a key molecular regulator of LZ in healthy liver and an important contributor to liver regeneration after partial hepatectomy (PH). Our research aims to unravel the long-standing conundrum of what then governs WNT/β-catenin signaling. Based on previously studies and our preliminary data, we hypothesize that hypoxia (low oxygen) and hypoxia-induced factor (HIF) signaling in zone 3 endothelial cells influence the zonated production of WNT ligands in healthy livers to maintain LZ, while global hypoxia after PH drives the increased production of WNT ligands to facilitate liver regeneration. The outcomes of our research will provide novel insights into the role of hypoxia in regulating LZ and regeneration after PH. These findings could be an important foundation for the development of innovative approaches to treat chronic liver diseases