Ezetimibe impairs transcellular lipid trafficking and induces large lipid droplet formation in intestinal absorptive epithelial cells.

Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1) protein, which mediates intracellular cholesterol trafficking from the brush border membrane to the endoplasmic reticulum, where chylomicron assembly takes place in enterocytes or in the intestinal absorptive epithelial cells. Cholesterol is a minor lipid constituent of chylomicrons; however, whether or not a shortage of cholesterol attenuates chylomicron assembly is unknown. The aim of this study was to examine the effect of ezetimibe, a potent NPC1L1 inhibitor, on trans-epithelial lipid transport, and chylomicron assembly and secretion in enterocytes. Caco-2 cells, an absorptive epithelial model, grown onto culture inserts were given lipid micelles from the apical side, and chylomicron-like triacylglycerol-rich lipoprotein secreted basolaterally were analyzed after a 24-h incubation period in the presence of ezetimibe up to 50 µM. The secretion of lipoprotein and apolipoprotein B48 were reduced by adding ezetimibe (30% and 34%, respectively). Although ezetimibe allowed the cells to take up cholesterol normally, the esterification was abolished. Meanwhile, oleic acid esterification was unaffected. Moreover, ezetimibe activated sterol regulatory element-binding protein 2 by approximately 1.5-fold. These results suggest that ezetimibe limited cellular cholesterol mobilization required for lipoprotein assembly. In such conditions, large lipid droplet formation in Caco-2 cells and the enterocytes of mice were induced, implying that unprocessed triacylglycerol was sheltered in these compartments. Although ezetimibe did not reduce the post-prandial lipid surge appreciably in triolein-infused mice, the results of the present study indicated that pharmacological actions of ezetimibe may participate in a novel regulatory mechanism for the efficient chylomicron assembly and secretion.

Pandemic (H1N1) 2009 in pregnant Japanese women in Hokkaido.

AIM: No maternal mortality from pandemic (H1N1) 2009 occurred in Japan. However, the reasons for this lack of maternal deaths remain unknown. This study was performed to investigate how many pregnant women were infected, how many women took antiviral drugs for prophylaxis or treatment, and the rate of vaccination effectiveness. MATERIAL AND METHODS: A questionnaire study was given to 20500 postpartum women before leaving obstetric facilities between December 2009 and May 2010 in Hokkaido, asking about antiviral drugs, vaccination, and infection with pandemic (H1N1) 2009. RESULTS: Approximately one-third (n=7535) of women given the questionnaires responded. Of these, 268 women (3.5%) indicated that they had contracted influenza. 353 (4.7%) women took antiviral drugs for prophylaxis after close contact with an infected person and 140 (39.7%) of 353 women finally contracted influenza during or after prophylaxis with antiviral drugs, accounting for 52.2% (140/268) of all patients. 229 (85.4%) of 268 patients took antiviral drug for treatment and 6 (2.2%) needed hospitalization, but not mechanical ventilation or intensive care unit. 196 of 268 (73.1%) patients were already infected before the availability of a vaccine. Among 7328 candidates for vaccination, 4921 (67.2%) were vaccinated. Infection occurred in 0.22% (11/4921) and 2.1% (50/2407) of vaccinated and non-vaccinated women, respectively. CONCLUSION: Frequent use of antiviral drugs for prophylaxis and treatment may partially explain the low infection rate and no maternal mortality from pandemic (H1N1) 2009 in Japan. Vaccination reduced infection by 89% in pregnant Japanese women.