Novel modulators of lipoprotein metabolism : implications for steatohepatitis and atherosclerosis

The studies described in this thesis have contributed to the discovery of CETP as a biomarker for the hepatic macrophage content, a hallmark of NASH for which no non-invasive diagnostic method is currently available, and discovery of novel therapeutic modalities for atherosclerosis and NASH. First of all, we gained more insight into the true cellular origin of CETP (i.e. the liver macrophage), and the mechanisms underlying the CETP-lowering effects of HDL-raising agents (i.e. by reducing the hepatic macrophage content). We extrapolated the association between the reduction of hepatic lipid content and plasma CETP concentration upon lipid-lowering interventions from mice to humans. Furthermore, we demonstrated the role of CETP in discrepant effects of rHDL on VLDL metabolism between mice and humans, and reported a species difference in the central regulation of hepatic VLDL metabolism by NPY between mice and rats, which underscores a general concern in animal research in view of extrapolating findings from specific animal studies to explain observations done in humans. Additionally, we demonstrated that CORT has long-lasting beneficial effects on atherosclerosis development suggesting a possibility for therapeutic application of anti-inflammatory agents in CVD. Finally, we described GLP-1 receptor agonism as a novel strategy to improve lipid metabolism and hepatic inflammation, which may result in novel strategies to treat both atherosclerosis and NASH