Emerging Roles of Liver Sinusoidal Endothelial Cells in Nonalcoholic Steatohepatitis

Simple Summary Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome. With the prevalence of obesity and type 2 diabetes, NAFLD is becoming the most common liver disorder worldwide. More than 10% of NAFLD patients progress to an inflammatory and fibrotic form called nonalcoholic steatohepatitis (NASH), which can lead to end-stage liver disease. Liver sinusoidal endothelial cells (LSEC) are highly specialized cells located at the interface between the flowing blood in the liver and the other liver cells. The current review highlights the recent knowledge of the role of LSEC in the development of NASH, and how LSEC change their structure and function during NAFLD progression. Moreover, the review discusses the pathogenic role of nanometer-sized particles called extracellular vesicles that mediate intercellular communication in the NASH liver. The current manuscript has a special emphasis on the role of adhesion molecules expressed on the LSEC surface in the recruitment of circulating leukocytes to the liver, a critical step in liver inflammation in NASH. Furthermore, the review shed some lights on LSEC-targeted potential therapeutic strategies in NASH. Nonalcoholic steatohepatitis (NASH) has become a growing public health problem worldwide, yet its pathophysiology remains unclear. Liver sinusoidal endothelial cells (LSEC) have unique morphology and function, and play a critical role in liver homeostasis. Emerging literature implicates LSEC in many pathological processes in the liver, including metabolic dysregulation, inflammation, angiogenesis, and carcinogenesis. In this review, we highlight the current knowledge of the role of LSEC in each of the progressive phases of NASH pathophysiology (steatosis, inflammation, fibrosis, and the development of hepatocellular carcinoma). We discuss processes that have important roles in NASH progression including the detrimental transformation of LSEC called capillarization, production of inflammatory and profibrogenic mediators by LSEC as well as LSEC-mediated angiogenesis. The current review has a special emphasis on LSEC adhesion molecules, and their key role in the inflammatory response in NASH. Moreover, we discuss the pathogenic role of extracellular vesicles and their bioactive cargos in liver intercellular communication, inflammation, and fibrosis. Finally, we highlight LSEC-adhesion molecules and derived bioactive product as potential therapeutic targets for human NASH.