Abstract
Reverse cholesterol transport (RCT) can proceed through the classic hepatobiliary route or through the nonbiliary transintestinal cholesterol efflux (TICE) pathway. Scavenger receptor class B type I (SR-BI) plays a critical role in the classic hepatobiliary route of RCT. However, the role of SR-BI in TICE has not been studied. To examine the role of intestinal SR-BI in TICE, sterol balance was measured in control mice and mice transgenically overexpressing SR-BI in the proximal small intestine (SR-BI(hApoCIII-ApoAIV-Tg)). SR-BI(hApoCIII-ApoAIV-Tg) mice had significantly lower plasma cholesterol levels compared with wild-type controls, yet SR-BI(hApoCIII-ApoAIV-Tg) mice had normal fractional cholesterol absorption and fecal neutral sterol excretion. Both in the absence or presence of ezetimibe, intestinal SR-BI overexpression had no impact on the amount of cholesterol excreted in the feces. To specifically study effects of intestinal SR-BI on TICE we crossed SR-BI(hApoCIII-ApoAIV-Tg) mice into a mouse model that preferentially utilized the TICE pathway for RCT (Niemann-Pick C1-like 1 liver transgenic), and likewise found no alterations in cholesterol absorption or fecal sterol excretion. Finally, mice lacking SR-BI in all tissues also exhibited normal cholesterol absorption and fecal cholesterol disposal. Collectively, these results suggest that SR-BI is not rate limiting for intestinal cholesterol absorption or for fecal neutral sterol loss through the TICE pathway.
Highlights
Reverse cholesterol transport (RCT) can proceed through the classic hepatobiliary route or through the nonbiliary transintestinal cholesterol efflux (TICE) pathway
Several groups have hypothesized a role for Scavenger receptor class B type I (SR-BI) in intestinal cholesterol absorption [36, 55, 56, 59, 65], studies where cholesterol absorption was quantified in mouse models of SR-BI deficiency [57] and transgenic overexpression (Figs. 1, 2, 4) have not supported such a role
The major findings of our present studies are the following: 1) endogenous SR-BI protein expression in the small intestine is barely detectable when compared with very abundant levels in the liver (Fig. 1A, B); 2) endogenous and ectopically expressed SR-BI localizes to both apical and basolateral membranes in enterocytes (Fig. 1B); 3) SR-BIhApoCIII-ApoAIV-Tg mice have reduced total plasma cholesterol and high density lipoprotein cholesterol (HDLc) levels compared with WT littermates [59] (Fig. 1C); 4) intestinal overexpression of SR-BI does not alter intestinal cholesterol absorption either in the absence or presence of the cholesterol absorption inhibitor EZE (Fig. 2); and 5) intestinal overexpression of SR-BI does not increase TICE in mice with substantially reduced contribution of the biliary pathway for RCT (NPC1L1LiverTg) (Fig. 4)
Summary
Reverse cholesterol transport (RCT) can proceed through the classic hepatobiliary route or through the nonbiliary transintestinal cholesterol efflux (TICE) pathway. SR-BIhApoCIII-ApoAIV-Tg mice had significantly lower plasma cholesterol levels compared with wild-type controls, yet SRBIhApoCIII-ApoAIV-Tg mice had normal fractional cholesterol absorption and fecal neutral sterol excretion. Both in the absence or presence of ezetimibe, intestinal SR-BI overexpression had no impact on the amount of cholesterol excreted in the feces. Even with the substantial LDLc lowering achieved with statin therapy, CVD-associated mortality and morbidity has been reduced by only ف30% [1, 2] Given this unmet therapeutic need, major interest has shifted toward developing high density lipoprotein cholesterol (HDLc)-elevating agents, because HDLc was shown to be an even stronger predictor than LDLc for CVD in a number of large population studies including the Framingham Heart Study [3]. A critical checkpoint in this process occurs in the hepatocyte, where cholesterol may be converted to bile acids or directly secreted into bile as free cholesterol (FC) [7, 8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
