Cytochrome P450 3A (CYP3A) enzymes constitute an important detoxification system that contributes to primary metabolism of more than half of all prescribed medications. To investigate the physiological and pharmacological roles of CYP3A, we generated Cyp3a-knockout (Cyp3a -/-) mice lacking all functional Cyp3a genes. Cyp3a -/-mice were viable, fertile, and without marked physiological abnormalities. However, these mice exhibited severely impaired detoxification capacity when exposed to the chemotherapeutic agent docetaxel, displaying higher exposure levels in response to both oral and intravenous administration. These mice also demonstrated increased sensitivity to docetaxel toxicity, suggesting a primary role for Cyp3a in xenobiotic detoxification. To determine the relative importance of intestinal versus hepatic Cyp3a in first-pass metabolism, we generated transgenic Cyp3a -/-mice expressing human CYP3A4 in either the intestine or the liver. Expression of CYP3A4 in the intestine dramatically decreased absorption of docetaxel into the bloodstream, while hepatic expression aided systemic docetaxel clearance. These results suggest that CYP3A expression determines impairment of drug absorption and efficient systemic clearance in a tissue-specific manner. The genetic models used in this study provide powerful tools to further study CYP3A-mediated xenobiotic metabolism, as well as interactions between CYP3A and other detoxification systems.

AimsProprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher risk of atherosclerosis. In this study, the AT04A anti-PCSK9 vaccine was evaluated for its therapeutic potential in ameliorating or even preventing coronary heart disease in the atherogenic APOE*3Leiden.CETP mouse model.Methods and resultsControl and AT04A vaccine-treated mice were fed western-type diet for 18 weeks. Antibody titres, plasma lipids, and inflammatory markers were monitored by ELISA, FPLC, and multiplexed immunoassay, respectively. The progression of atherosclerosis was evaluated by histological analysis of serial cross-sections from the aortic sinus. The AT04A vaccine induced high and persistent antibody levels against PCSK9, causing a significant reduction in plasma total cholesterol (−53%, P < 0.001) and LDLc compared with controls. Plasma inflammatory markers such as serum amyloid A (SAA), macrophage inflammatory protein-1β (MIP-1β/CCL4), macrophage-derived chemokine (MDC/CCL22), cytokine stem cell factor (SCF), and vascular endothelial growth factor A (VEGF-A) were significantly diminished in AT04A-treated mice. As a consequence, treatment with the AT04A vaccine resulted in a decrease in atherosclerotic lesion area (−64%, P = 0.004) and aortic inflammation as well as in more lesion-free aortic segments (+119%, P = 0.026), compared with control.ConclusionsAT04A vaccine induces an effective immune response against PCSK9 in APOE*3Leiden.CETP mice, leading to a significant reduction of plasma lipids, systemic and vascular inflammation, and atherosclerotic lesions in the aorta.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potential novel strategy for treatment of CVD. Alirocumab is a fully human PCSK9 monoclonal antibody in phase 3 clinical development. We evaluated the antiatherogenic potential of alirocumab in APOE*3Leiden.CETP mice. Mice received a Western-type diet and were treated with alirocumab (3 or 10 mg/kg, weekly subcutaneous dosing) alone and in combination with atorvastatin (3.6 mg/kg/d) for 18 weeks. Alirocumab alone dose-dependently decreased total cholesterol (−37%; −46%, P < 0.001) and TGs (−36%; −39%, P < 0.001) and further decreased cholesterol in combination with atorvastatin (−48%; −58%, P < 0.001). Alirocumab increased hepatic LDL receptor protein levels but did not affect hepatic cholesterol and TG content. Fecal output of bile acids and neutral sterols was not changed. Alirocumab dose-dependently decreased atherosclerotic lesion size (−71%; −88%, P < 0.001) and severity and enhanced these effects when added to atorvastatin (−89%; −98%, P < 0.001). Alirocumab reduced monocyte recruitment and improved the lesion composition by increasing the smooth muscle cell and collagen content and decreasing the macrophage and necrotic core content. Alirocumab dose-dependently decreases plasma lipids and, as a result, atherosclerosis development, and it enhances the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice. In addition, alirocumab improves plaque morphology.

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 Ϫ77%, PϽ0.001) and total cholesterol (up to -66%, PϽ0.001). Concomitantly, niacin dose-dependently increased HDL-cholesterol (up to ϩ87%, PϽ0.001), plasma apoAI (up to ϩ72%, PϽ0.001), as well as the HDL particle size. In contrast, in 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 Ϫ88%; PϽ0.01) as well as plasma CETP mass (up to Ϫ45%, PϽ0.001) and CETP activity (up to Ϫ52%, PϽ0.001). Additionally, niacin dose-dependently decreased the clearance of apoAI from plasma and reduced the uptake of apoAI by the kidneys (up to Ϫ90%, PϽ0.01). yslipidemia is an important risk factor for the development of cardiovascular disease (CVD). Although lowering of LDL-cholesterol (C) by eg, statins reduces CVD risk by approximately 30%, substantial residual cardiovascular risk remains, even with very aggressive reductions in levels of LDL-C. [1][2][3] Because of clinical studies, which have shown that HDL-C, independently of LDL-C, is inversely correlated with the risk of CVD, 4,5 attention has shifted toward strategies for targeting HDL composition as adjunctive therapy to prevent and treat CVD. Current strategies to mildly increase HDL-C levels include aggressive overall lifestyle modification (ie, exercise, diet, weight loss, and smoking cessation), and modest increases in HDL-C levels are achieved with statins 6 and fibrates (5% to 10%). 7 Conclusion-Niacin markedly increases HDL-cholesterol in See accompanying article on page 1892Niacin (nicotinic acid, vitamin B3) has been described to exhibit lipid-modifying capacities already since the 1950s. Since then various (clinical) studies have shown the beneficial effects of niacin on plasma lipid levels. Treatment with niacin alone was associated with a 27% reduction in nonfatal myocardial infarction and it reduced all cause mortality by 11%. 8,9 In combination with colestipol (FATS trial) or simvastatin (HATS trial), niacin reduced cardiac events by as much as 80% to 90%. 10,11 These potent atherogenic properties of niacin are thought to be attributable to its marked HDLelevating effect (ϩ20% to ϩ30%), besides it potent effect on reducing plasma TG (Ϫ40% to Ϫ50%) and LDL-C (Ϫ20%). 7,12 In fact, niacin is currently the most effective therapy for elevating HDL-C.The mechanism underlying the ability of niacin to reduce the plasma (V)LDL level has been well studied. By selective binding to GPR109A on adipocytes, niacin suppresses hormone sensitive triglyceride lipase (HSL) activit...