The Role of the Liver Sinusoidal Endothelial Cells in the Pathophysiology of Insulin Resistance

Ageing is associated with increased prevalence of metabolic syndrome, as well as impaired glucose metabolism, hyperinsulinemia and insulin resistance. The mechanism underlying these associations is poorly understood and is likely to be complex and multifactorial. The liver is the key target for insulin action and while the endothelium has been shown to influence insulin activity in muscle and fat, the role of the liver sinusoidal endothelium on the action of insulin in the liver is unknown. The liver sinusoidal endothelium is unique: it is perforated with transcellular pores called fenestrations that facilitate unimpeded passage of substrates between blood and hepatocytes. A constellation of age-related morphological changes in the liver sinusoidal endothelium known as pseudocapillarisation have been described in various species including rats, baboons and humans. During ageing, the liver sinusoidal endothelium thickens, there is basement membrane deposition, and the fenestrations are significantly reduced in size and number (defenestration). Age-related pesudocapillarisation has been shown previously to impede the transfer of lipoproteins and medications across the hepatic sinusoidal endothelium. This thesis tests the hypothesis that changes in the ageing liver contribute to age-related insulin resistance, with alterations of the liver sinusoidal endothelial cell leading to age-related impairment of insulin action and insulin resistance/glucose metabolism. This work aims to improve the understanding of the effects of ageing processes in the liver on insulin action and glucose metabolism. It investigates the role of age-related pseudocapillarisation and the acutely induced poloxamer 407 (P407) model of defenestration in hepatic disposition of insulin and glucose metabolism. This thesis also investigates the effect of P407 on the relationship between membrane rafts and fenestrations in SKHep1 cells, a cell line of liver endothelial origin and isolated LSECs. Finally, the effects of dietary macronutrients and calorie intake on fenestrations in old age are examined. The work contained in this thesis aims to examine the role of age-related pseudocapillarisation in one of the major causes of age-related disease and disability, insulin resistance. In doing so it explores the potential mechanisms involved in these changes and how we may alter the progression of ageing through nutritional intervention