TY - JOUR
T1 - Intestinal cholesterol absorption is substantially reduced in mice deficient in both ABCA1 and ACAT2
AU - Temel, Ryan E.
AU - Lee, Richard G.
AU - Kelley, Kathryn L.
AU - Davis, Matthew A.
AU - Shah, Ramesh
AU - Sawyer, Janet K.
AU - Wilson, Martha D.
AU - Rudel, Lawrence L.
PY - 2005/11
Y1 - 2005/11
N2 - The process of cholesterol absorption has yet to be completely defined at the molecular level. Because of its ability to esterify cholesterol for packaging into nascent chylomicrons, ACAT2 plays an important role in cholesterol absorption. However, it has been found that cholesterol absorption is not completely inhibited in ACAT2-deficient (ACAT2 KO) mice. Because ABCA1 mRNA expression was increased 3-fold in the small intestine of ACAT2 KO mice, we hypothesized that ABCA1-dependent cholesterol efflux sustains cholesterol absorption in the absence of ACAT2. To test this hypothesis, cholesterol absorption was measured in mice deficient in both ABCA1 and ACAT2 (DKO). Compared with wild-type, ABCA1 KO, or ACAT2 KO mice, DKO mice displayed the lowest level of cholesterol absorption. The concentrations of hepatic free and esterified cholesterol and gallbladder bile cholesterol were significantly reduced in DKO compared with wild-type and ABCA1 KO mice, although these measures of hepatic cholesterol metabolism were very similar in DKO and ACAT2 KO mice. We conclude that ABCA1, especially in the absence of ACAT2, can have a significant effect on cholesterol absorption, although ACAT2 has a more substantial role in this process than ABCA1.
AB - The process of cholesterol absorption has yet to be completely defined at the molecular level. Because of its ability to esterify cholesterol for packaging into nascent chylomicrons, ACAT2 plays an important role in cholesterol absorption. However, it has been found that cholesterol absorption is not completely inhibited in ACAT2-deficient (ACAT2 KO) mice. Because ABCA1 mRNA expression was increased 3-fold in the small intestine of ACAT2 KO mice, we hypothesized that ABCA1-dependent cholesterol efflux sustains cholesterol absorption in the absence of ACAT2. To test this hypothesis, cholesterol absorption was measured in mice deficient in both ABCA1 and ACAT2 (DKO). Compared with wild-type, ABCA1 KO, or ACAT2 KO mice, DKO mice displayed the lowest level of cholesterol absorption. The concentrations of hepatic free and esterified cholesterol and gallbladder bile cholesterol were significantly reduced in DKO compared with wild-type and ABCA1 KO mice, although these measures of hepatic cholesterol metabolism were very similar in DKO and ACAT2 KO mice. We conclude that ABCA1, especially in the absence of ACAT2, can have a significant effect on cholesterol absorption, although ACAT2 has a more substantial role in this process than ABCA1.
KW - ATP binding cassette transporter A1
KW - ATP-binding cassette transporter G5
KW - Acyl-coenzyme axholesterol acyltransferase
KW - Gallbladder bile
KW - Liver
KW - Niemann-Pick CL-like 1
KW - Plasma lipoproteins
UR - http://www.scopus.com/inward/record.url?scp=27444432557&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27444432557&partnerID=8YFLogxK
U2 - 10.1194/jlr.M500232-JLR200
DO - 10.1194/jlr.M500232-JLR200
M3 - Article
C2 - 16150828
AN - SCOPUS:27444432557
SN - 0022-2275
VL - 46
SP - 2423
EP - 2431
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 11
ER -