1C) as well as triglyceride levels (20 �� 1 mg/dl, Fig 1D) were

1C) as well as triglyceride levels (20 �� 1 mg/dl, Fig. 1D) were significantly decreased (each P < 0.001). Although hepatic SR-BI expression showed a constant decline from day 3 to day 14, plasma total cholesterol and triglyceride levels did not follow this trend. On day 7, plasma total cholesterol (86 �� 8 mg/dl, Fig. 1C) and triglycerides (114 �� Ivacaftor EC50 6 mg/dl, Fig. 1D) increased significantly compared with day 3 values (P < 0.01). However, this was followed by a decrease on day 14 [cholesterol: 73 �� 6 mg/dl, triglycerides: 84 �� 5 mg/dl (P < 0.05 compared with day 7), Fig. 1C, D]. FPLC analysis revealed a striking increase in levels of apoB-containing lipoproteins on day 7 compared with day 3 and day 14 (Fig. 2B). These results led us to hypothesize that SR-BI might be involved in VLDL production in addition to functioning as an uptake receptor for cholesterol (3�C6).

Further experiments therefore focused on exploring the metabolic effects of SR-BI using adenovirus-mediated overexpression on day 7 after AdSR-BI injection as well as SR-BI knockout mice. Fig. 2. Cholesterol distribution over the different subfractions determined by FPLC analysis either in (A) SR-BI knockout mice and wild-type controls administered the empty control adenovirus AdNull, or (B) wild-type mice on different days after injection with … Hepatic SR-BI expression promotes VLDL triglyceride and apoB production Because the finding of increased levels of apoB-containing lipoproteins on day 7 after AdSR-BI administration in the presence of high levels of hepatic SR-BI expression cannot be explained by SR-BI increasing the catabolic rate of VLDL, we first determined hepatic VLDL production rates.

In mice overexpressing SR-BI, hepatic VLDL triglyceride production rates were significantly increased compared with controls (143 �� 2 vs. 108 �� 2 mg/kg/h, P < 0.001, Fig. 3A). In addition, the production of VLDL apoB48 (1760 �� 121 vs. 1028 �� 81 cpm, P < 0.001, Fig. 3B) as well as apoB100 (905 �� 75 vs. 642 �� 44 cpm, P < 0.05, Fig. 3B) were significantly higher in AdSR-BI injected mice. Complementing these results in SR-BI overexpressing mice, VLDL triglyceride production rates in SR-BI knockouts were significantly lower than in wild-type controls (106 �� 6 vs. 120 �� 3 mg/kg/h, P < 0.05, Fig. 3C). Also, production of VLDL apoB48 (1178 �� 70 vs. 897 �� 78 cpm, P < 0.05, Fig.

3D) was significantly lower in SR-BI knockouts whereas apoB100 showed a trend toward a decrease (707 �� 57 vs. 535 �� 44 cpm, P = 0.052, Fig. 3D). These data indicate that SR-BI expression is positively related to hepatic VLDL-triglyceride as well as VLDL apoB production. Fig. 3. SR-BI expression is associated with altered hepatic VLDL production. A: Hepatic VLDL-TG production rates and (B) hepatic VLDL-apoB production Dacomitinib rates in wild-type mice on day 7 following injection with either AdSR-BI or the control adenovirus AdNull. C: …

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