HEPATIC LIPID METABOLISM: THE ROLES OF ACAT2 AND ABCG5/G8 IN THE DEVELOPMENT AND PREVENTION OF DISEASE

Cholesterol is one of the most thoroughly researched organic molecules, however emerging information is regularly added to the literature about the function of cholesterol in biological systems. Elevated plasma cholesterol and particularly cholesterol on the low-density lipoprotein (LDL) has been directly correlated with risk for development of atherosclerosis, the disease process that can lead to many of the complications associated with heart disease. Acyl-CoA:Cholesterol Acyl Transferase isoform 2 (ACAT2) is an enzyme that has been implicated in the development and progression of atherosclerosis and is a target for pharmacological intervention. This dissertation describes a role for ACAT2 and the hepatic ACAT2-derived cholesteryl esters (CE) in hepatic triglyceride metabolism. Data are presented which indicate that CE can limit the mobilization of triglyceride from the liver and lead to hepatic steatosis associated with non-alcoholic fatty liver disease (NAFLD). Adenosine triphosphate (ATP) Binding Cassette transporters G5 and G8 (ABCG5/G8 or G5G8) form an apical membrane obligate heterodimeric protein complex that transports intracellular free sterols to bile or the intestinal lumen. Data are presented to show that transgenic over-expression of G5G8 does not affect the NAFLD phenotype in ACAT2 modified mice. Disruption of G5G8 in mice replicates the rare autosomal recessive human disease β-sitosterolemia, which is identified by high retention of dietary plant sterols (phytosterols). Further, data are presented that indicate that ACAT2 does not efficiently esterify plant sterols in vivo. In collaborative studies, we also showed that mice that retain phytosterols (G5G8-/-) do not have altered bile acid composition, compared to animals that readily excrete these non-absorbable sterols. Consistent with theβ-sitosterolemia phenotype, mice lacking G5G8 retained high concentrations of phytosterol after dietary challenge with phytosterol, displayed lipid metabolic disturbances, and cytotoxicity in several organs. We observed that mice lacking G5G8 developed altered lipoprotein profiles including an apolipoprotein E-rich lipoprotein (ERL), hepatosplenomegaly, hemolytic anemia, and myocardial infarction in response to high dietary phytosterol retention. Our results show that ACAT2 and G5G8 have contrasting roles in modulating free sterol metabolism, suggesting a critical role for hepatic expression of these proteins in the development or prevention (respectively) of whole-body lipid homeostatic diseases.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2009

Author dc:creator

• Alger, Heather

• Biochemistry

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10339/14739

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/14739