Brown fat activation attenuates atherosclerosis development by accelerating triglyceride-rich lipoprotein turnover and/or stimulation of reverse cholesterol transport via the SRB1 (scavenger... Show moreBrown fat activation attenuates atherosclerosis development by accelerating triglyceride-rich lipoprotein turnover and/or stimulation of reverse cholesterol transport via the SRB1 (scavenger receptor class B type 1). The aim of this study was to investigate the specific role of hepatic SRB1 in the atheroprotective properties of brown fat activation.APOE*3-Leiden.CETP mice, a well-established model of human-like lipoprotein metabolism andatherosclerosis, were treated with vehicle or adenoassociated virus serotype 8-short hairpin RNA, which decreased hepatic SRB1 protein levels by 40% to 55%. After 2 weeks, mice without or with hepatic SRB1 knockdown were treated with vehicle or the β3-adrenergic receptor agonist CL316 243 to activate brown fat for 4 weeks to determine HDL (highdensity lipoprotein) catabolism and for 9 weeks to evaluate atherosclerosis. Surprisingly, hepatic SRB1 knockdown additively improved the beneficial effects of β3-adrenergic receptor agonism on atherosclerosis development. In fact, hepatic SRB1 knockdown per se not only increased HDL-cholesterol levels but also reduced plasma triglyceride and non-HDL-cholesterol levels, thus explaining the reduction in atherosclerosis development. Mechanistic studies indicated that this is due to increased lipolytic processing and hepatic uptake of VLDL (very low density lipoprotein) by facilitating VLDL-surface transfer to HDL.Hepatic SRB1 knockdown in a mouse model with an intact ApoE (apolipoprotein E)-LDLR (low density lipoprotein receptor) clearance pathway, relevant to human lipoprotein metabolism, reduced atherosclerosis and improved the beneficial effect of brown fat activation on atherosclerosis development, explained by pleiotropic effects of hepatic SRB1 knockdown on lipolytic processing and hepatic uptake of VLDL. Brown fat activation could thus be an effective strategy to treat cardiovascular disease also in subjects with impaired SRB1 function. Show less
The research described in this thesis focussed on the role of apolipoproteins in lipid metabolism, inflammation and bacterial sepsis, with specific emphasis on apoCI. From studies in human APOC1_... Show moreThe research described in this thesis focussed on the role of apolipoproteins in lipid metabolism, inflammation and bacterial sepsis, with specific emphasis on apoCI. From studies in human APOC1_-transgenic and apoc1-/- mice, we were able to identify apoCI as a potent inhibitor of triglyceride hydrolysis by inhibiting lipoprotein lipase. Since APOC1 mice have thus increased VLDL levels, and VLDL protects against bacterial infection, we studied whether apoCI could play a role in inflammation and infection. We found that apoCI was able to bind lipopolysaccharide (LPS), the main toxic component of Gram-negative bacteria. Interestingly, although other apolipoproteins which have been studied have anti-inflammatory properties, we found that apoCI is a pro-inflammatory protein. By enhancing the biological response towards LPS and Gram-negative bacteria, apoCI dose-dependently improved the anti-bacterial attack, and protected against intrapulmonal Klebsiella pneumoniae-induced sepsis. Consistent with these experimental findings we also found that subjects with high plasma apoCI levels were less prone to infection-related mortality during follow-up, independent of plasma lipid levels. Likewise, survivors of severe sepsis showed higher plasma apoCI levels as compared to non-survivors, again independent of lipid levels. Taken together, our findings indicate that apoCI is an important determinant of the inflammatory response in mice and humans. Show less
