Primary and secondary hypertriglyceridemia is common in the general population, but the biochemical basis for this disease is largely unknown. With the use of transgenic technology, two lines of mice were created that express the human apolipoprotein CIII gene. One of these mouse lines with 100 copies of the gene was found to express large amounts of the protein and to be severely hypertriglyceridemic. The other mouse line with one to two copies of the gene expressed low amounts of the protein, but nevertheless manifested mild hypertriglyceridemia. Thus, overexpression of apolipoprotein CIII can be a primary cause of hypertriglyceridemia in vivo and may provide one possible etiology for this common disorder in humans.

ABSTRACT:Raltegravir is a potent human immunodeficiency virus 1 (HIV-1) integrase strand transfer inhibitor that is being developed as a novel anti-AIDS drug. The absorption, metabolism, and excretion of raltegravir were studied in healthy volunteers after a single oral dose of 200 mg (200 Ci) of [ 14 C]raltegravir. Plasma, urine, and fecal samples were collected at specified intervals up to 240 h postdose, and the samples were analyzed for total radioactivity, parent compound, and metabolites. Radioactivity was eliminated in substantial amounts in both urine (32%) and feces (51%). The elimination of radioactivity was rapid, since the majority of the recovered dose was attributable to samples collected through 24 h. In extracts of urine, two components were detected and were identified as raltegravir and the glucuronide of raltegravir (M2), and each accounted for 9% and 23% of the dose recovered in urine, respectively. Only a single radioactive peak, which was identified as raltegravir, was detected in fecal extracts; raltegravir in feces is believed to be derived, at least in part, from the hydrolysis of M2 secreted in bile, as demonstrated in rats. The major entity in plasma was raltegravir, which represented 70% of the total radioactivity, with the remaining radioactivity accounted for by M2. Studies using cDNA-expressed UDP-glucuronosyltransferases (UGTs), form-selective chemical inhibitors, and correlation analysis indicated that UGT1A1 was the main UGT isoform responsible for the formation of M2. Collectively, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.HIV-1 is the etiologic agent of AIDS. HIV infection continues to be a major problem with more than 40 million individuals currently infected with the virus worldwide ([UNAIDS] Joint United Nations Programme on HIV/AIDS 2006 Report on the global AIDS epidemic. http://www.unaids.org). The current standard of care for treating HIV infection, called HAART, is a regimen typically consisting of three or more drugs from two or more available classes. Current HAART medications (of which there are Ͼ20) include members from four classes of drugs: nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Although the advent of HAART has significantly reduced AIDS-related morbidity and mortality, it has been estimated that 78% of treatment-naive patients harbor viruses that are resistant to one or more of the three classes (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors) (Richman, 2001;Little et al., 2002). Because of this factor and issues of tolerability, toxicity, and patient noncompliance due to the rigorous drug administration schedules, there is a critical need for new HIV therapies capable of addressing the deficiencies inherent with currently used drugs.Integrase is one of the three HIV-1 enzymes required for viral replication (Esposito and Cr...

Atherosclerosis is a chronic inflammatory disease that develops in response to injury to the vessel wall, and is augmented by hypercholesterolemia. To further delineate the role of the immune system and local factors in this process, we assessed the effects of the immunosuppressant sirolimus (Rapamycin, RAPAMUNE â , Wyeth, Collegeville, PA) on atherosclerosis in the apoE-deficient (apoE KO) mouse, a well-accepted model of cardiovascular disease. ApoE KO mice were fed a high fat diet and sirolimus was administered. After 12 weeks, atherosclerotic lesions and plasma lipoproteins were measured. The expression of cytokines associated with atherosclerosis was also examined. All groups demonstrated plasma total cholesterol (TC) >1100 mg/dL. Sirolimus treatment was associated with a 30% increase in LDL-cholesterol (LDLc) and a dose-dependent elevation in HDL-cholesterol (HDLc). Despite increased LDLc, aortic atherosclerosis was markedly reduced in all sirolimus-treated groups. Sirolimus treatment resulted in decreased expression of IL-12p40, IFN-g and IL-10 mRNA. In contrast, TGF-b1 was elevated. Sirolimus significantly reduced atherosclerosis in apo E-KO mice; this effect is independent of, and obviates, elevated plasma TC and LDLc. Sirolimus might therefore be of benefit on atherosclerosis in patients undergoing therapy, independent of any impact on circulating lipids.

IntroductionIn humans, diets high in saturated fat and cholesterol raise HDL-cholesterol (HDL-C) levels. To explore the mechanism, we have devised a mouse model that mimics the human situation. In this model, HuAITg and control mice were studied on low fat (9% cal)-low cholesterol (57 mg/1,000 kcal) (chow) and high fat (41% cal)-high cholesterol (437 mg/1,000 kcal) (milk-fat based) diets. The mice responded to increased dietary fat by increasing both HDL-C and apo A-I levels, with a greater increase in HDL-C levels. In most societies today, there is a well-known inverse correlation between coronary heart disease risk and HDL cholesterol (HDL-C)' levels ( 1-3). However, paradoxically, diets high in saturated fat and cholesterol, which increase atherosclerosis risk, raise HDL-C levels (4-9). To explore the mechanism for this phenomenon and perhaps gain greater insight into the role of HDL in heart disease, in a previous human metabolic study (9), we measured the turnover of the major HDL apolipoproteins, apo A-I and apo A-II, in 13 subjects consuming low fat (9% calories)-low cholesterol (40 mg/ 1,000 kcal) and high fat (42% calories)-high cholesterol (215 mg/ 1,000 kcal) diets. The dietary fat challenge increased HDL-C 40%, apo A-I 30% (both P < 0.001 ), with no change in apo A-II levels. The turnover studies indicated a 17% increase in apo A-I transport rate (TR) and a 10% decrease in apo A-I fractional catabolic rate (FCR). Individual changes in HDL-C levels correlated with changes in apo A-I TR (r = 0.79, P < 0.001) but not FCR (r = -0.04). This study suggested that dietary fat both increases the TR and decreases the FCR ofapo A-I with perhaps a larger effect on the TR (9). Since clinical studies do not allow further examination of how dietary fat influences apo A-I metabolism nor do they permit studies ofHDL CE metabolism, in the current study, to pursue these questions, an animal model was created. Mice were used because of the availability of human apo A-I transgenic (HuAITg) lines (10, 11). These animals express significant amounts ofhuman apo A-I in plasma, and for reasons not yet understood, they have greatly diminished mouse apo A-I levels (1 1-13). Accompanying this exchange of human for mouse apo A-I is a change from normal mouse HDL, which has a single major size distribution ofHDL particles to humanlike HDL characterized by two or more major size distributions, principally HDL2b and HDL3J (11)(12)(13). Thus, HuAITg mice might be a better model in which to study the dietary fat-HDL relationship.As in the human metabolic study, mice were fed low fat (9% calories)-low cholesterol (57 mg/ 1,000 kcal) and high fat (41% calories), high cholesterol (437 mg/ 1,000 kcal) diets. In contrast to previously used high fat-high cholesterol diets that have lowered HDL-C and apo A-I levels in some strains ofmice

Raltegravir is an HIV integrase inhibitor that is metabolized through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1, and its use is anticipated in combination with atazanavir (a uridine diphosphate glucuronosyltransferase 1A1 inhibitor). Two pharmacokinetic studies of healthy subjects assessed the effect of multiple-dose atazanavir or ritonavir-boosted atazanavir on raltegravir levels in plasma. Atazanavir and atazanavir plus ritonavir modestly increase plasma levels of raltegravir.