5-fold increased, whereas biliary pospholipid (103.2 �� 14.9 vs. 23.0 �� 1.6 nmol/min/100 g BW, P < 0.001) and cholesterol secretion (11.73 �� 2.36 vs. 2.15 �� 0.17 nmol/min/100 Temsirolimus mw g BW, P < 0.01) were 4.5-fold and 5.5-fold higher in the T1DM group, respectively (Fig. 2B�CD). Fig. 2. T1DM mice have increased biliary sterol secretion. Continuous bile cannulation was performed on day 10 after injection with either alloxan (n = 5) or PBS (n = 6). Bile was collected during 30 min. Bile production and biliary bile acid, phospholipid, and ... Fecal BA excretion was significantly higher in diabetic mice (2.85 �� 0.20 vs. 2.01 �� 0.12 ��mol/day, P < 0.01, Fig. 3A). However, fecal neutral sterol excretion did not change significantly (4.04 �� 0.28 vs. 3.46 �� 0.23 ��mol/day, P = 0.13, Fig.
3B), conceivably attributable to increased intestinal cholesterol absorption as indicated by higher plasma campesterol/cholesterol ratios in T1DM mice compared with controls (12.5 �� 1.1 vs. 8.4 �� 0.4 �� 10?3, P < 0.01) as well as by a 2.1-fold higher intestinal fractional cholesterol absorption in direct measurements (74 �� 12 vs. 35 �� 8%, P < 0.05). Fig. 3. Fecal bile acid excretion is increased in T1DM mice, while fecal neutral sterol excretion is unaltered. Feces of individually housed mice (n = 8 per group) were collected over a period of 24 h, starting on day 8 after alloxan or PBS injection. Fecal samples ... Hepatic gene expression analysis indicates increased BA synthesis in type I diabetic mice The hepatic expression of the major transporters for biliary cholesterol, ATP-binding cassette transporter G5 (Abcg5) and Abcg8 was increased by 34% (P < 0.
05) and 33% (P < 0.01), respectively (Table 2). The expression of the biliary phospholipid transporter Abcb4 (Mdr2) was increased by 19% (P < 0.05), whereas the expression of the BA transporter Abcb11 (Bsep) was not different (Table 2). The expression of HMG-CoA reductase (Hmgcr) remained unchanged, indicating that cholesterol synthesis rates were not altered in T1DM mice. Identical plasma lathosterol/cholesterol ratios in T1DM mice and controls as measure of endogenous cholesterol synthesis rates further supported this conclusion (1.6 �� 10?4 �� 0.2 �� 10?4 vs. 1.6 �� 10?4 �� 0.2 �� 10?4). However, a 9-fold (P < 0.01) increase in the expression of Cyp7a1 and a 1.7-fold elevated expression of Cyp8b1 (P < 0.
05) indicated increased BA synthesis in diabetic mice. TABLE 2. Hepatic mRNA expression levels at day 10 after injection with alloxan or PBS Macrophage-to-feces RCT is decreased in type I diabetic mice Biliary sterol secretion, either as free cholesterol or after metabolic conversion to BAs, is a critical step in RCT Carfilzomib (7, 8). Therefore, a macrophage-to-feces RCT experiment was performed to investigate whether increased biliary sterol secretion in diabetic mice would translate into increased RCT.