**7. References**

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Alvarez, E., Roncero, I, Chowen, J.A., Vázquez, P. & Blázquez, E. (2002). Evidence that glucokinase regulatory protein is expressed and interacts with glucokinase in rat brain. *Journal of neurochemistry,* Vol. 80, No. 1, (January 2002), pp. 45-53, ISSN 0022- 3042

gluconeogenic pathway. Its transcription is regulated by insulin, so that it is repressed in fed state and induced during fasting. However, glucose induces transcription of this enzyme although the physiological significance of this induction is still not resolved (Nordlie, 2010). Finally glucose-6-phosphatase deficiency causes severe hyperlipidemia and hepatic steatosis (Bandsma, 2002, 2008), therefore giving rise that this enzyme may also participate or influence the GK/GKRP system in the regulation of hepatic glucose fate. To support this hypothesis, Reiling and colleagues described combined effects of single-nucleotide polymorphisms in GK, GKRP and glucose-6-phosphatase on fasting plasma glucose and type 2 diabetes (Reiling, 2009). Therefore, it is a field that needs

Subtle changes in GK activity or in GKRP function have consequences in glucose and lipid metabolism. However, further studies must be done to completely understand the mechanism underlying GK/GKRP biology. Our results on increasing GK protein in the liver of both healthy and insulin-deficient mice (lacking endogenous GK) resulted in dyslipidemia. On the other hand, our analysis of the metabolic consequences of GK-GKRP deregulation by overexpressing a GK activating mutant (GKA456V) in the liver of both healthy and type 1 diabetic mice demonstrates an impact on glycaemia in the absence of dyslipidemia or hepatic lipid deposition. These data provide novel insights into the capacity of the complex GK-GKRP to influence the fate of metabolized glucose in the liver, providing

We conclude that GKRP regulation impairment and GK-A456V altered kinetics greatly influence liver metabolism, in line with results in humans carrying a mutant GKRP (Køster, 2005; Sparsø, 2007; Vaxillaire, 2008 & Orho-Melander, 2008). Besides, it suggests that activating GK exclusively in the liver could be a feasible strategy to funnel excess glucose from the diet out of circulation, widening the scope for GK synthetic activators research.

We thank Sandra M. Ocampo, Francesc X. Blasco and the Research Support Services from the Biology Unit of Bellvitge (University of Barcelona) for their technical assistance, and Dr. Maria Molas for invaluable assistance in reviewing the manuscript. A.V.A received a fellowship from DURSI (Generalitat de Catalunya), A.M.L. received a fellowship from F.P.I. (Ministerio de Educación y Ciencia, Spain). This study was supported by a grant from the

Agius, L. (2008). Glucokinase and molecular aspects of liver glycogen metabolism*. The Biochemical Journal,* Vol.414, No.1, (August 2008), pp. 1-18, ISSN 0264-6021 Alvarez, E., Roncero, I, Chowen, J.A., Vázquez, P. & Blázquez, E. (2002). Evidence that

glucokinase regulatory protein is expressed and interacts with glucokinase in rat brain. *Journal of neurochemistry,* Vol. 80, No. 1, (January 2002), pp. 45-53, ISSN 0022-

a framework for further research on GK activating drugs in the liver.

Ministerio de Educación y Ciencia (BFU2006-02802 and BFU2009-07506).

further exploration.

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**13** 

*1Australia 2Norway 3New Zealand* 

**Liver Sinusoidal Endothelial Cells and** 

Dmitri Svistounov1, Svetlana N. Zykova1,2, Victoria C. Cogger1,

*1Centre for Education and Research on Ageing and ANZAC Research Institute,* 

*2Department of Nephrology, University Hospital of Northern Norway, Tromsø,* 

Dyslipidaemia is a well-described major independent risk factor for cardiovascular disease (Lin et al.). It is well established that the liver plays the central role in lipid metabolism and liver malfunction is one of the main sources of dyslipidemia (Watson et al., 2003). However, most of the studies so far have focused on the role of hepatocytes in lipid turnover. Indeed, hepatocytes do play a central role in liver lipid metabolism, but they are not alone. Hepatocytes do not have direct contact with the circulation. Any blood-borne lipoprotein particle must first pass through a filter comprised of a layer of endothelial cells, lining the walls of liver sinusoids, before it can contact the liver parenchyma. Likewise, lipoproteins remodelled or synthesized by the liver encounter the same barrier before they reach

The hepatic sinusoids are small blood vessels, comparable to capillaries in size, that perfuse the hepatocytes. However, unlike the capillaries in other tissues, sinusoids are formed by a discontinuous endothelium that lacks any significant underlying basement membrane. Walls of sinusoids are formed by the liver sinusoidal endothelial cells (LSECs). LSECs are separated from liver parenchyma by the perisinusoidal extravascular space, known as the space of Disse (Figure 1A). LSECs contribute only 15-20% of all liver cells but comprise 70% of the population of sinusoidal cells in the liver (Arias, 1990; Arii and Imamura, 2000; Blouin

The LSECs are perforated by trans-cytoplasmic pores called fenestrae, which do not have any intervening diaphragmatic membrane, and thus are fully patent holes through the cell (Figure 1A-B). This specialized lace-like morphology of the LSECs minimizes any barrier to

**1. Introduction** 

systemic circulation.

**2. The structure of the hepatic sinusoid** 

et al., 1977; Knook and Sleyster, 1976).

**Regulation of Blood Lipoproteins** 

Alessandra Warren1, Aisling C. McMahon1, Robin Fraser 3 and David G. Le Couteur1

*3University of Otago, Christchurch,* 

*University of Sydney and Concord RG Hospital, Sydney,* 

