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HEP_23408_sm_supfig1.tif292KSupplemental Figure 1. Plasma lipoprotein profile of control and colesevelam-treated lean and db/db mice. VLDL-TG was reduced in diabetic mice upon treatment. No changes in VLDL-TG levels were observed in lean mice. Plasma from 6 animals per group was pooled and separated by fast protein liquid chromatography (FPLC) on a Superose 6 column.
HEP_23408_sm_supfig2.tif305KSupplemental Figure 2. Average decay curves of [2H4]cholate from the plasma compartment expressed as the natural logarithm of the atom% excess (LnAPE) value. From this curve the fractional turnover rate (FTR, calculated from the slope of the curve) and the pool size (y-intercept) can be calculated. The synthesis rate is determined by multiplying FTR and pool size. For details see Hulzebos et al. 23
HEP_23408_sm_supfig3.tif1017KSupplemental Figure 3. Hepatic expression of Fxr and Fxr-target genes. Hepatic expression of Fxr and of the well-defined Fxr-target genes Shp, Ntcp and Bsep were unaffected in colesevelam-treated lean mice compared to controls. In db/db mice, however, hepatic expression of Shp and Ntcp were reduced and increased, respectively, which is indicative of reduced FXR-signaling. Expression of Bsep was unchanged in colesevelam HCl-treated db/db mice compared to controls. Gene expression levels are presented as relative expression normalized to 18S. N=6 animals per group. Significant differences within or between groups are indicated # and *, respectively.
HEP_23408_sm_supfig4.tif2920KSupplemental Figure 4. Colesevelam-treatment does not affect hepatic expression of Lxr and Lxr-target genes. Gene expression levels are presented as relative expression normalized to 18S. N=6 animals per group. Significant differences within or between groups are indicated # and *, respectively
HEP_23408_sm_supfig5.tif501KSupplemental Figure 5. Working model reduced sinusoidal bile salt gradient in colesevelam-treated mice. colesevelam-treatment impairs re-uptake of bile salts in the intestine and, hence, reduces the flux of recirculating bile salts to the liver. The subsequent reduction in sinusoidal bile salt gradient affects expression and regulation of genes involved in (bile salt) metabolism along the hepatic lobule as was shown for expression of Cyp7a1. In normal conditions, this gene is located in pericentral hepatocytes.44 Upon sequestrant treatment, it translocates to a larger area of the liver lobulus with more involvement of periportally localized hepatocytes. 45 The amount of bile salt molecules reabsorbed in ilea of colesevelam-treated mice was decreased by ∼30% with a subsequent reduction in plasma bile salt levels and, hence, reduced bile salt signaling in periportal hepatocytes. Additionally, we speculate that newly synthesized bile salts, which represent a large fraction of the bile salt pool of colesevelam-treated mice, might exert differential signaling actions compared to recirculating bile salts.
HEP_23408_sm_suptable.doc39KSupplemental Table 1. Fecal and biliary bile salt composition as percentage of total bile salts. Secondary bile salts are marked *. Values are presented as mean ± SD. N=6 animals per group. +; colesevelam-treated
HEP_23408_sm_suptext.doc34KSupplemental Materials and Methods

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