The role and ultrastructure of the liver sinusoidal endothelial cell in fasting, hepatoxicity, and ageing

Abstract

The majority of liver studies focus on the hepatocyte however the work of this thesis investigates the vital role of the liver sinusoidal endothelial cell (LSEC). LSECs line the liver sinusoids forming a protective barrier between the blood and hepatocytes. The LSEC cytoplasm resembles a sieve, perforated with thousands of transcellular pores of approximately 50-150 nm in diameter called fenestrations, and is underlined by a very sparse extracellular matrix. This facilitates the virtually unimpeded passage of fluid and substances smaller than fenestrations from the blood such as drugs and nutrients, and size-dependent filtration of lipoproteins, to and from hepatocytes. Fenestrations are dynamic structures, in that their size and number can be modulated by hormones, drugs, hepatotoxins, and diseases. Reduction of LSEC fenestration size and number (defenestration) is associated with ageing and pathological states, and is also a cause of hyperlipidemia and reduced drug clearance, thus changes in LSEC morphology can affect the entire organism. This thesis aims to broaden knowledge of the role and ultrastructure of the LSEC in physiological and toxicological states by investigating: whether there is fenestration modulation during fasting that could facilitate increased nutrient exchange between the blood and hepatocytes; whether changes to LSEC ultrastructure during acetaminophen hepatotoxicity are consistent with exacerbation of liver injury and/or with the facilitation of liver regeneration after severe necrosis; whether a substance that targets the LSEC could have a therapeutic benefit in acetaminophen hepatotoxicity by protecting the microvasculature from damage; whether isolation and culture of LSECs from ageing rats maintain the ageing (defenestrated) phenotype, and thus whether it is a valid method to study therapeutic substances in vitro that could reverse defenestration-related ailments associated with normal ageing.