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Background Lipopolysaccharide ( LPS ) decreases hepatic CETP (cholesteryl ester transfer protein) expression albeit that the underlying mechanism is disputed. We recently showed that plasma CETP is mainly derived from Kupffer cells ( KC s). In this study, we investigated the role of KC subsets in the mechanism by which LPS reduces CETP expression. Methods and Results In CETP ‐transgenic mice, LPS markedly decreased hepatic CETP expression and plasma CETP concentration without affecting hepatic macrophage number. This was paralleled by decreased expression of the resting KC markers C‐type lectin domain family 4, member f ( Clec4f ) and V‐set and immunoglobulin domain containing 4 ( Vsig4 ), while expression of the infiltrating monocyte marker lymphocyte antigen 6 complex locus C ( Ly6C ) was increased. Simultaneously, the ratio of plasma high‐density lipoprotein‐cholesterol over non–high‐density lipoprotein‐cholesterol transiently increased. After ablation hepatic macrophages via injection with liposomal clodronate, the reappearance of hepatic gene and protein expression of CETP coincided with Clec4f and Vsig4, but not Ly6C. Double‐immunofluorescence staining showed that CETP co‐localized with Clec4f + KC s and not Ly6C + monocytes. In humans, microarray gene‐expression analysis of liver biopsies revealed that hepatic expression and plasma level of CETP both correlated with hepatic VSIG4 expression. LPS administration decreased the plasma CETP concentration in humans. In vitro experiments showed that LPS reduced liver X receptor‐mediated CETP expression. Conclusions Hepatic expression of CETP is exclusively confined to the resting KC subset (ie, F4/80 + Clec4f + Vsig4 + Ly6C − ). LPS activated resting KC s, leading to reduction of Clec4f and Vsig4 expression and reduction of hepatic CETP expression, consequently decreasing plasma CETP and raising high‐density lipoprotein (HDL)‐cholesterol. This sequence of events is consistent with the anti‐inflammatory role of HDL in the response to LPS and may be relevant as a defense mechanism against bacterial infections.

Objective— Niacin potently decreases plasma triglycerides and LDL-cholesterol. In addition, niacin is the most potent HDL-cholesterol–increasing drug used in the clinic. In the present study, we aimed at elucidation of the mechanism underlying its HDL-raising effect. Methods and Results— In APOE*3Leiden transgenic mice expressing the human CETP transgene, niacin dose-dependently decreased plasma triglycerides (up to −77%, P P P P APOE*3Leiden mice, not expressing CETP, niacin also decreased total cholesterol and triglycerides but did not increase HDL-cholesterol. In fact, in APOE*3Leiden.CETP mice, niacin dose-dependently decreased the hepatic expression of CETP (up to −88%; P P P P Conclusion— Niacin markedly increases HDL-cholesterol in APOE*3Leiden.CETP mice by reducing CETP activity, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool, and increases HDL-apoAI by decreasing the clearance of apoAI from plasma.

Objectives: Brown adipose tissue (BAT) recently emerged as a novel player in lipoprotein metabolism. BAT combusts high amounts fatty acids into heat resulting in reduced plasma triglyceride (TG) levels as well as obesity. However, the precise role of BAT in cholesterol metabolism and atherosclerosis development remains unclear. We aimed to assess the effect of stimulating BAT activity by ß3-adrenergic receptor (ß3-AR) agonism on lipoprotein metabolism and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism. Methods and results: Mice were fed a Western-type diet to induce dyslipidemia and were treated subcutaneously with the selective ß3-AR agonist CL316243 (3x20 μg/week) or vehicle for 10 weeks. ß3-AR agonism reduced total fat mass (-59%) and white adipose tissue (WAT) pad size (-40%). ß3-AR agonism decreased the size of intracellular lipid vacuoles in BAT, and increased UCP-1 expression in WAT, indicating activation of brown adipocytes ( i.e. BAT) as well as their precursors ( i.e. WAT). These effects were accompanied by increased uptake of glycerol tri[ 3 H]oleate from VLDL-like particles by BAT (+125%) and by WAT (+120%) as well as fatty acid oxidation (+25%) as determined by indirect calorimetry. In line with these data, activation of BAT decreased plasma levels of TG (-46%) and (V)LDL-cholesterol (-24%) and increased HDL-cholesterol (+23%), accompanied by increased reverse cholesterol transport (+2.5-fold). As a consequence of improving lipoprotein metabolism, BAT activation reduced atherosclerosis development (-43%) as well as lesion severity, indicated by more mild type I-III lesions (+64%) and reduced severe type IV-V lesions (-66%), in the aortic root. These effects were dependent on a functional hepatic apoE-LDLr clearance pathway, as BAT activation in apoe -/- and ldlr -/- mice lowered plasma TG levels but did not attenuate hypercholesterolemia and atherosclerosis Conclusion: We demonstrate that activation of BAT via the ß3-AR is a powerful tool to reduce dyslipidemia and protect against atherosclerosis. These findings indicate that activation of BAT is a promising novel strategy to combat dyslipidemia and cardiovascular disease.