title: Niacin reduces plasma CETP levels by diminishing liver macrophage content in CETP transgenic mice.
abstract: The anti-dyslipidemic drug niacin has recently been shown to reduce the hepatic expression and plasma levels of CETP. Since liver macrophages contribute to hepatic CETP expression, we investigated the role of macrophages in the CETP-lowering effect of niacin in mice. In vitro studies showed that niacin does not directly attenuate CETP expression in macrophages. Treatment of normolipidemic human CETP transgenic mice, fed a Western-type diet with niacin for 4 weeks, significantly reduced the hepatic cholesterol concentration (-20%), hepatic CETP gene expression (-20%), and plasma CETP mass (-30%). Concomitantly, niacin decreased the hepatic expression of CD68 (-44%) and ABCG1 (-32%), both of which are specific markers for the hepatic macrophage content. The decrease in hepatic CETP expression was significantly correlated with the reduction of hepatic macrophage markers. Furthermore, niacin attenuated atherogenic diet-induced inflammation in liver, as evident from decreased expression of TNF-alpha (-43%). Niacin similarly decreased the macrophage markers and absolute macrophage content in hyperlipidemic APOE*3-Leiden.CETP transgenic mice on a Western-type diet. In conclusion, niacin decreases hepatic CETP expression and plasma CETP mass by attenuating liver inflammation and macrophage content in response to its primary lipid-lowering effect, rather than by attenuating the macrophage CETP expression level.
authors: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
authors: Zhaosha
authors: Z
authors: Li
authors: Yanan
authors: Y
authors: Wang
authors: Ronald J
authors: RJ
authors: van der Sluis
authors: José W A
authors: JW
authors: van der Hoorn
authors: Hans M G
authors: HM
authors: Princen
authors: Miranda
authors: M
authors: Van Eck
authors: Theo J C
authors: TJ
authors: Van Berkel
authors: Patrick C N
authors: PC
authors: Rensen
authors: Menno
authors: M
authors: Hoekstra
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000633:toxicity; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009525:Niacin / Q000494:pharmacology* / Q000633:toxicity; D057093:Orphan Nuclear Receptors / Q000378:metabolism
chemical_list: D053318:Apolipoprotein E3; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D009525:Niacin