Staff surgeon, post doc
Karolinska Institute, Karolinska University Hospital
Hepatocyte transplantation normalizes hypercholesterolemia and aortic accumulation of cholesterol in apolipoprotein E knockout mice
Carl Jorns1, Masaaki Watanabe1, Lisa-Mari Mörk1, Lilian Larsson2, Helen Zemack1, Raoul Kuiper3, Stephen Strom3, Bo-Göran Ericzon1, Paolo Parini2, Ewa Ellis1.
1Transplantation Surgery, Karolinska Institute, Stockholm, Sweden; 2Clinical Chemistry, Karolinska Institute, Stockholm, Sweden; 3Pathology, Karolinska Institute, Stockholm, Sweden
Apolipoprotein E (ApoE) plays a major role in cholesterol metabolism by facilitating removal of lipoprotein remnants. ApoE is mainly produced by hepatocytes, but also to a lesser degree in other tissues and cells. A deficiency in this protein leads to severe hyperlipidemia and atherosclerosis in humans and ApoE (-/-) mice. Replacing ApoE production via gene therapy or bone marrow transplantation normalizes hyperlipidemia and prevents atherosclerosis in ApoE (-/-) mice. The aim of the present study was to investigate if transplantation of wildtype hepatocytes into ApoE (-/-) mice improves hyperlipidemia and prevents atherosclerosis. Hepatocytes isolated from C57bl/6 mice were transplanted into retrorsine-treated ApoE (-/-) mice. After hepatocyte transplantation, serum ApoE concentration continuously increased until reaching 3.5-55% of wildtype levels. Hepatic ApoE mRNA expression reached 22-55% of wildtype levels 12 weeks after transplantation. Total cholesterol concentration and lipoprotein profiles improved gradually and normalized 5-7 weeks after transplantation. ApoE mRNA in situ hybridization showed extensive liver repopulation with multiple clones of engrafted donor hepatocytes. Hepatocyte-transplanted animals exhibited significantly less cholesteryl ester deposition in the thoracic aorta than controls. Taken together, the results indicate that hepatocyte transplantation with retrorsine pretreatment in ApoE(-/-) mice results in robust liver repopulation, the normalization of cholesterol metabolism, and prevention of atherosclerosis.
11:00 - 12:30
|Hepatocyte Transplantation||Hepatocyte transplantation normalizes hypercholesterolemia and aortic accumulation of cholesterol in apolipoprotein E knockout mice||Room 111-112|