001). Phospholipids remained unchanged, but hepatic triglyceride content was higher in AdSR-BI injected mice (P < 0.05). However, in SR-BI knockout selleck compound mice hepatic total and free cholesterol contents were also significantly increased (P < 0.05), in agreement with previously published data (19). In the SR-BI knockout model, liver phospholipids and triglycerides did not change compared with wild-type controls. TABLE 2. Liver weight and liver lipid composition in mice on the C57BL/6 genetic background with different hepatic SR-BI expression SR-BI expression alters hepatic gene expression and MTP activity Hepatic gene expression levels in the different models investigated are given in Table 3. The expression of MTP and apoE did not change in response to altered SR-BI expression.

Hepatic expression of SREBP1c as well as FAS was unchanged in mice injected with AdSR-BI; however, both genes were significantly increased in SR-BI knockout mice compared with controls (P < 0.01, Table 3). Interestingly, there was a consistent change in the expression of SREBP2 and its target genes HMG-CoA reductase and LDLR. The mRNA expression of all three genes was decreased in response to SR-BI overexpression (P < 0.01, Table 3), as was the level of nuclear SREBP2 (Fig. 5), indicating alterations in endoplasmic reticulum (ER) cholesterol content dependent on SR-BI expression. On the other hand, expression of SREBP2, HMG-CoA reductase, and LDLR was significantly increased in SR-BI knockout mice (P < 0.01, Table 3). TABLE 3. Hepatic gene expression levels in mice on the C57BL/6 genetic background with different hepatic SR-BI expression Fig.

5. Nuclear levels of SREBP2 protein are decreased in response to SR-BI overexpression. Western blots for nuclear SREBP2 were performed as detailed in Experimental Procedures using livers from mice injected with either AdNull or AdSR-BI as indicated (day … Because MTP plays a central role in VLDL production, we also assessed hepatic MTP activity in the different groups of mice in addition to measuring mRNA expression. SR-BI overexpression resulted in increased MTP activity (1094 �� 45 vs. 821 �� 59%transfer/mg/h, P < 0.01, Fig. 6A), whereas MTP activity was decreased in the SR-BI knockout mice (376 �� 30 vs. 626 �� 94%transfer/mg/h, Anacetrapib P < 0.05, Fig. 6B) each compared with the respective control groups. Fig. 6. Hepatic MTP activity depending on the hepatic SR-BI expression level. A: Livers from wild-type mice analyzed on day 7 following injection with either AdSR-BI or the control adenovirus AdNull. B: Livers from SR-BI knockout mice and wild-type controls; …