Transintestinal Cholesterol Excretion Is an Active Metabolic Process Modulated by PCSK9 and Statin Involving ABCB1

Abstract

Objective-Transintestinal cholesterol excretion (TICE) is an alternate pathway to hepatobiliary secretion. Our study aimed at identifying molecular mechanisms of TICE. Approach and Results-We studied TICE ex vivo in mouse and human intestinal explants, and in vivo after bile diversion and intestinal cannulation in mice. We provide the first evidence that both low-density lipoprotein (LDL) and high-density lipoprotein deliver cholesterol for TICE in human and mouse jejunal explants at the basolateral side. Proprotein convertase subtilisin kexin type 9 (PCSK9) −/− mice and intestinal explants show increased LDL-TICE, and acute injection of PCSK9 decreases TICE in vivo, suggesting that PCSK9 is a repressor of TICE. The acute repression was dependent on the LDL receptor (LDLR). Further, TICE was increased when mice were treated with Lovastatin. These data point to an important role for LDLR in TICE. However, LDLR −/− mice showed increased intestinal LDL uptake, contrary to what is observed in the liver, and tended to have higher TICE. We interpret these data to suggest that there might be at least 2 mechanisms contributing to TICE; 1 involving LDL receptors and other unidentified mechanisms. Acute modulation of LDLR affects TICE, but chronic deficiency is compensated for most likely by the upregulation of the unknown mechanisms. Using mice deficient for apical multidrug active transporter ATP-binding cassette transporter B1 a and b, and its inhibitor, we show that these apical transporters contribute significantly to TICE. Conclusions-TICE is operative in human jejunal explants. It is a metabolically active process that can be acutely regulated, inversely related to cholesterolemia, and pharmacologically activated by statins. Beside the liver, LDLR is expressed in many tissues, including the intestine where it is localized on the basolateral side of enterocytes.13 Experiments in rats infused with LDL showed that intestinal LDLR mediates 60% of the LDL uptake. 14In the liver and in the intestine, the quantity of cell surface LDLR results from a balance between its synthesis and degradation. Cellular cholesterol depletion and cholesterol synthesis inhibitors like statins increase the LDLR transcription via the activation of the sterol response element binding protein 2 pathway.11 Plasma proprotein convertase subtilisin kexin type 9 (PCSK9) induces the LDLR degradation because it binds to the extracellular domain of the LDLR and prevents its recycling to the cell surface.15 Thus, mice deficient in PCSK9 have more LDLR protein in the liver 16 and in the intestine. 17 The functional importance of intestinal LDLR and its circulating regulator PCSK9 in TICE remains to be explored.Efflux of free cholesterol from the apical side of the enterocytes mainly takes place via ATP-binding cassette transporter G5/ATP-binding cassette transporter G8 (ABCG5/G8).18 TICE is reduced by only 40% in ABCG5-deficient mice, 8 suggesting that TICE-derived cholesterol exit enterocytes via other cholesterol transporters. P-Glycoprotein (P-gp; m...

Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin

“…In line with our data, full absence of PCSK9 was recently reported not to be associated with hepatic lipid accumulation or fecal excretion of cholesterol (43). However, contrasting data in PCSK9 −/− mice demonstrated increased LDL-C excretion via the transintestinal cholesterol excretion pathway and subsequently mildly increased fecal neutral sterol loss, with unfortunately no data on fecal bile acid loss (44). As opposed to PCSK9 inhibition by alirocumab in the present study, lack of PCSK9 was reported to increase fecal bile acid output (43).…”

PCSK9 and LDLR degradation

“…The negative effect of PCSK9 on RCT may not only be mediated by LDLR lowering in liver. Le May et al [55 ▪▪ ] showed that PCSK9-mediated LDLR degradation in small intestine represses the delivery of LDL-C and HDL-C for trans-intestinal cholesterol excretion, a nonbiliary route of fecal neutral sterol loss that contributes approximately 30% of total sterol excretion in mice, or 60% upon liver X receptor activation [56]. An important future direction is to further delineate the roles of PCSK9 in liver and intestinal mechanisms of RCT.…”

Extended-Release Niacin/Laropiprant Improves Overall Efficacy of Postprandial Reverse Cholesterol Transport

“…37 It is interesting to note that fasting HDL particles isolated from ERN/LRPT-treated patients displayed a reduced HDL-CE liver delivery as compared with their equivalent counterparts isolated from patients before ERN/LRPT treatment; however, an equivalent increase in HDL-mediated RCT to feces was observed, thus suggesting that niacin might increase cholesterol elimination via a liver-independent mechanism, such as the transintestinal cholesterol excretion pathway. 38 Human ApoB/CETP double transgenic mice fed with niacin showed significant reduction in P2Y13 gene expression in both the liver and intestine. The niacin-induced reduction in P2Y13 expression in the liver has been previously proposed as potential mechanism underlying HDL-C raising effect of niacin.…”