The contribution of vascular adhesion protein-1 to glucose and lipid homeostasis in the liver

Karim, Sumera (2013). The contribution of vascular adhesion protein-1 to glucose and lipid homeostasis in the liver. University of Birmingham. Ph.D.

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Abstract

NAFLD is characterized by simple steatosis, which can progress to chronic inflammation and fibrosis. Vascular Adhesion Protein-1 (VAP-1) is an adhesion molecule with semicarbazide- sensitive amine oxidase (SSAO) activity, which is also expressed as a soluble protein in serum (sVAP-1) and elevated in inflammatory liver diseases such as NAFLD. VAP-1 has been shown to modulate glucose and lipid uptake in muscle and adipose tissue and thus we investigated whether it may contribute to glucose and lipid homeostasis in human liver tissue. Recreating the multicellular liver environment using an ex-vivo model we have shown that activation of VAP-1 by its substrate methylamine leads to activation of NF-κB, glucose uptake and lipid accumulation in the human liver with changes in transporter expression of GLUT4, GLUT10 and GLUT13, as well as FABP2, LRP1, FATP2, FATP3, FATP4 and FATP6. We have also documented changes in transporter expression profiles in human disease. In conclusion, we demonstrate for the first time global alterations in cellular expression of glucose and lipid transporter proteins in NASH. We confirm that VAP-1 is elevated in disease and that SSAO activity of VAP-1 results in enhanced hepatic glucose and lipid accumulation with changes in transporter expression. Thus we propose that bioactive metabolites of SSAO activity contribute to the metabolic derangement evident in fatty liver disease.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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