Sugar Crush: Metabolism-Induced Sinusoidal Endothelial Cell Defenestration as Critical Determinant of Fatty Liver Disease Progression

The buildup of excess fat in the liver when no alcohol consumption is involved is called Non-Alcoholic Fatty Liver Disease (NAFLD), a condition that can lead to progressive liver disease, cancer, and liver failure. The disease affects 1 in 3 people worldwide, and with no medication currently available, it is one of the major clinical challenges of the 21st century. Despite decades of research, the mechanisms involved in the initiation and progression of the disease have remained unsolved. Thus far research has mainly focused on the hepatocytes, the most abundant and main functional cells of the liver. However, hepatocytes lie behind the capillary blood vessels which are made of liver sinusoidal endothelial cells (LSECs). LSECs facilitate the transfer of molecules and nutrients between blood and the hepatocytes. Interestingly, the progression of NAFLD coincides with changes to LSEC form and function, which has not been investigated for links to the progression of NAFLD. This project aims to investigate the metabolism-based molecular mechanisms underlying changes in LSEC form and function during initiation and progression of NAFLD. Understanding the role of LSEC changes in NAFLD progression may dramatically shift our understanding of the natural history of NAFLD while providing novel therapeutic avenues. The project uses animal models and human clinical samples, and combine multidisciplinary approaches in cellular biology, genetics, and physics, and the expertise of a research team composed of top-of-the-field local, national and international collaborators. Our results point to a shift in the metabolism of glucose as well as the amino acid methionine as driving forces in the alteration of LSEC form and function. This project is currently investigating these cellular metabolic changes in the context of NAFLD progression and potential dietary and pharmaceutical targets for novel therapeutic avenues.

Non-alcoholic fatty liver disease (NAFLD) is one of the major clinical challenges of the 21st century. For decades research focused on hepatocytes, but failed to unravel the mechanisms behind disease progression, while largely overlooking the role of the endothelial cell of the liver, the LSEC. LSECs, which form the walls of the hepatic sinusoids, contain small pores, or fenestrations, which facilitate the transfer of substrates between blood and hepatocytes. A ubiquitous clinical observation in the progression of NAFLD is the loss of fenestrations, which importantly precedes the onset of fibrosis, collagen "scar" tissue that is eliminated primarily by LSECs. The mechanisms responsible for LSEC defenestration in NAFLD progression have yet to be described. We aim to investigate the metabolism-based molecular mechanisms underlying changes in LSEC morphology and function during initiation and progression of NAFLD, using animal models and human clinical samples. The main challenge is the need to independently manipulate and probe metabolic pathway utilization and morphological and functional changes in these cells. To overcome this challenge, the project will combine multidisciplinary approaches in cellular biology, genetics, and physics, and the expertise of a research team composed of top-of-the-field local, national and international collaborators. The project is anticipated to make a tremendous scientific impact, and have the potential for clinical ramifications.