Akitoshi Sano, MD, PhD

American Liver Foundation Postdoctoral Research Fellowship Award
$25,000 over one year

Mayo Clinic, Rochester

Endothelial Cells Glycogen Synthase Kinase 3 Promotes Liver Inflammation and Fibrosis in Metabolic Dysfunction-Associated Steatohepatitis

Mentor: Samar Ibrahim, MB, ChB

As the number of obese individuals rises, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is also increasing worldwide. Among the subtypes of MASLD, the more aggressive form, metabolic dysfunction-associated steatohepatitis (MASH), is associated with liver injury and inflammation, and may lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Therefore, there is a pressing need for the development of effective treatments. However, the current standard treatments rely mainly on dietary and exercise interventions, and there is a lack of specific therapeutic options. Liver sinusoidal endothelial cells (LSECs) form the lining of the smallest blood vessels (hepatic sinusoids) in the liver. During MASH, toxic lipids induce LSEC dysfunction, thereby causing proinflammatory responses. Glycogen synthase kinase 3 beta (GSK3 ), a kinase involved in various signaling pathways related to cell metabolism, immune cell adhesion, and inflammation, is considered a potential therapeutic target for MASH. Based on previous research and our preliminary data, we hypothesize that GSK3 in LSECs acts as a hub regulating mitochondrial function and immune cells, especially dendritic cells, the principal antigen-presenting cells that shape the immune niche, in MASH. To examine this hypothesis, we will employ lipotoxic models in both cell and animal experiments and conduct comprehensive and detailed analyses. Aim 1 will discuss how GSK3 governs mitochondrial dynamics and DC maturation/activation in lipotoxic LSEC–DC interaction. Aim 2 will define the impact of endothelial Gsk3 deletion in the animal MASH model, integrating immune profiling by mass cytometry and spatial transcriptomics to map LSEC–DC communication. Through these analyses, we aim to evaluate whether GSK3and its associated pathways could serve as viable therapeutic targets for MASH.