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  • The intestinal cholesterol absorption markers sitosterol and


    The intestinal cholesterol Vancomycin hydrochloride pathway markers sitosterol and campesterol to cholesterol levels were significantly lower in Villin-Tgif1 mice compared to wild type mice, irrespective of diet. However, the decrease was less pronounced in Villin-Tgif1 mice fed a chow diet (∼20–30%) compared to mice fed a high-fat diet (∼40–50%). Similarly, the decrease in Npc1l1 mRNA expression levels was less pronounced in Villin-Tgif1 mice fed a chow (∼20%) compared to a high-fat (∼40%) diet. This may be one of the reasons why no significant effects on serum and tissue cholesterol levels, or cholesterol and bile acid synthesis were observed in Villin-Tgif1 fed a chow diet. Mice lacking Npc1l1 display >70% lower intestinal cholesterol absorption which is compensated for by higher cholesterol synthesis and results in an absence of significant effects on serum cholesterol levels [[8], [9], [10]]. In line with this, increased cholesterol synthesis (intestinal, hepatic, or whole-body) compensates for the lower intestinal cholesterol absorption, resulting in no significant differences in serum or tissue cholesterol levels in Villin-Tgif1 compared to wild type mice when fed a high-fat diet. Since humans are not able to upregulate cholesterol synthesis as efficiently as mice, it is still unclear whether upregulation of intestinal expression of TGIF1 would lead to decreased plasma cholesterol levels in humans. In our previous study [7], we found no significant differences in serum plant sterols or intestinal Tgif1 mRNA expression levels between Tgif1−/− and wild types (unpublished data). This may be due the few numbers of mice and our choice to feed the mice a chow diet, which we also found in this study results in less strong effects on serum plant sterols and intestinal Npc1l1 mRNA expression levels compared to feeding a high-fat diet. The lack of significant effects on serum and tissue cholesterol levels, or cholesterol and bile acid synthesis in Villin-Tgif1 fed a chow diet may also be due to a pathway termed transintestinal cholesterol efflux (TICE) [34]. Cholesterol is excreted by biliary secretion but can, at least in mice, also be excreted directly from enterocytes. A decrease in TICE would then compensate for the lower cholesterol absorption. Whether TICE is also a part of the compensatory mechanism in Villin-Tgif1 mice fed high-fat diet remains to be elucidated. Binding of PCSK9 to the LDL receptor increases its degradation and leads to increased plasma LDL cholesterol levels [35]. PCSK9 can also increase the production of apoB100 in hepatocytes, independently of the LDL receptor pathway [36]. Interestingly, PCSK9 is also expressed in the intestine and TICE has been reported to be increased in Pcsk9−/− mice [37]. Our finding of increased intestinal Pcsk9 mRNA expression levels in Villin-Tgif1 mice fed a regular chow and a high-fat diet thus further supports TICE as part of the compensatory mechanisms for the reduction in intestinal cholesterol absorption in Villin-Tgif1 mice. The lack of significant differences in serum PCSK9 levels may be explained by the fact that commercial available ELISA kits measure total PCSK9 levels, and thus do not distinguish between the active and the inactive forms of PCSK9. The relevance of TICE in humans as well as the role of TGIF1 in this process needs to be further investigated. The effects on intestinal expression of the LXR target genes ABCA1, ABCG5, and ABCG8 indicate some potential cross talk between TGIF1 and LXR. Indeed, LXRα has been shown to coprecipitate with TGIF1 and that the interaction was decreased by treatment with an LXRα ligand (GW3965), suggesting that TGIF1 can interact with LXRα and repress transcription [6]. Also, knockdown of TGIF1 in a mouse liver cell line (NMuLi) increased Abca1 and Abcg1 mRNA expression levels and knockdown of TGIF1 in a human liver cell line (HepG2) increased ABCA1 and SREBF1 expression levels [6]. Moreover Tgif1−/− mice, fed a high-fat, high-cholesterol diet (21% fat and 1.25% cholesterol) for 15 weeks, had decreased hepatic Cyp7a1 and increased Abcb4, Abcg8, Apoa4, and Apoc2 mRNA expression levels [6]. However, treatment of Tgif1−/− and wild type mice with a synthetic LXR agonist (T0901317) for three days resulted in few significant differences in hepatic mRNA expression levels [6].