Simultaneous Determination of Biliary and Intestinal Cholesterol Secretion Reveals That CETP (Cholesteryl Ester Transfer Protein) Alters Elimination Route in Mice

Abstract

Objective: Determine the impact of CETP (cholesteryl ester transfer protein) on the route of cholesterol elimination in mice. Approach and Results: We adapted our protocol for biliary cholesterol secretion with published methods for measuring transintestinal cholesterol elimination. Bile was diverted and biliary lipid secretion maintained by infusion of bile acid. The proximal small bowel was perfused with bile acid micelles. In high-fat, high-cholesterol–fed mice, the presence of a CETP transgene increased biliary cholesterol secretion at the expense of transintestinal cholesterol elimination. The increase in biliary cholesterol secretion was not associated with increases in hepatic SR-BI (scavenger receptor BI) or ABCG5 (ATP-binding cassette G5) ABCG8. The decline in intestinal cholesterol secretion was associated with an increase in intestinal Niemann-Pick disease, type C1, gene-like 1 mRNA. Finally, we followed the delivery of HDL (high-density lipoprotein) or LDL (low-density lipoprotein) cholesteryl esters (CE) from plasma to bile and intestinal perfusates. HDL-CE favored the biliary pathway. Following high-fat feeding, the presence of CETP directed HDL-CE away from the bile and towards the intestine. The presence of CETP increased LDL-CE delivery to bile, whereas the appearance of LDL-CE in intestinal perfusate was near the lower limit of detection. Conclusions: Biliary and intestinal cholesterol secretion can be simultaneously measured in mice and used as a model to examine factors that alter cholesterol elimination. Plasma factors, such as CETP, alter the route of cholesterol elimination from the body. Intestinal and biliary cholesterol secretion rates are independent of transhepatic or transintestinal delivery of HDL-CE, whereas LDL-CE was eliminated almost exclusively in the hepatobiliary pathway.

Dietary Lactic Acid Bacteria Modulate Yolk Components and Cholesterol Metabolism by Hmgr Pathway in Laying Hens

“…Bile acids, the major endproduct of cholesterol metabolism, are synthesized in the liver and secreted via bile into the intestine to aid the absorption of fat-soluble vitamins and dietary fat (Di Ciaula et al, 2017). Simultaneous measurements of biliary and intestinal cholesterol secretion in mice showed that plasma cholesteryl ester transfer protein (CETP) altered the route of cholesterol elimination from the body in mice fed a high fat, high cholesterol diet (Li et al, 2019). Overexpression of bile salt hydrolase by a Lactobacillus strain reduced cholesterol absorption and increased cholesterol catabolism in mice fed a high cholesterol diet (Wang et al, 2019c).…”

Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments

“…Obicetrapib is a CETP inhibitor, ezetimibe is a Niemann Pick C1-Like-1 inhibitor, and statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase. In addition to impairing the transfer of cholesteryl esters from HDL to ApoB-containing particles, CETP inhibition may also increase transintestinal cholesterol excretion, which would contribute to fecal sterol excretion, and upregulate scavenger receptor class B type 1 and hepatic LDL receptor expression [ 30 , 74 , 75 ]. Further, previous studies on CETP inhibitors have demonstrated that there is a substantially increased catabolic rate of LDL and ApoB, which is the primary metabolic basis for their low plasma levels.…”

“…These results indicate that the LDL receptor pathway may also be upregulated by CETP inhibition [ 76 – 78 ]. The combination of these actions will reduce circulating LDL-C concentrations [ 30 , 35 •, 74 , 75 ].

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Stigmasterol stimulates transintestinal cholesterol excretion independent of liver X receptor activation in the small intestine

“…An identically treated second cohort (n=7-8 per sex) underwent surgical assessment of biliary and intestinal cholesterol secretion rates as previously described with minor modifications. [30] Mice were anesthetized using 2% isoflurane (Henry Schein, Product Number 050033) and placed on a temperature-controlled heating pad system (Protech International Inc., TC-1000 Temperature Controller) to maintain a body temperature of 37 °C. Mice were supplied with oxygen (Scott Gross, Item Number 421) and isoflurane using a nose cone.…”