The critical role of neutral cholesterol ester hydrolase 1 in cholesterol removal from human macrophages.
BACKGROUND
Hydrolysis of intracellular cholesterol ester (CE) is the key step in the reverse cholesterol transport in macrophage foam cells. We have recently shown that neutral cholesterol ester hydrolase (Nceh)1 and hormone-sensitive lipase (Lipe) are key regulators of this process in mouse macrophages. However, it remains unknown which enzyme is critical in human macrophages and atherosclerosis.


OBJECTIVE
We aimed to identify the enzyme responsible for the CE hydrolysis in human macrophages and to determine its expression in human atherosclerosis.


RESULTS
We compared the expression of NCEH1, LIPE, and cholesterol ester hydrolase (CES1) in human monocyte-derived macrophages (HMMs) and examined the effects of inhibition or overexpression of each enzyme in the cholesterol trafficking. The pattern of expression of NCEH1 was similar to that of neutral CE hydrolase activity during the differentiation of HMMs. Overexpression of human NCEH1 increased the hydrolysis of CE, thereby stimulating cholesterol mobilization from THP-1 macrophages. Knockdown of NCEH1 specifically reduced the neutral CE hydrolase activity. Pharmacological inhibition of NCEH1 also increased the cellular CE in HMMs. In contrast, LIPE was barely detectable in HMMs, and its inhibition did not decrease neutral CE hydrolase activity. Neither overexpression nor knockdown of CES1 affected the neutral CE hydrolase activity. NCEH1 was expressed in CD68-positive macrophage foam cells of human atherosclerotic lesions.


CONCLUSIONS
NCEH1 is expressed in human atheromatous lesions, where it plays a critical role in the hydrolysis of CE in human macrophage foam cells, thereby contributing to the initial part of reverse cholesterol transport in human atherosclerosis.
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Japan.
Masaki
M
Igarashi
Jun-ichi
J
Osuga
Hiroshi
H
Uozaki
Motohiro
M
Sekiya
Shuichi
S
Nagashima
Manabu
M
Takahashi
Satoru
S
Takase
Mikio
M
Takanashi
Yongxue
Y
Li
Keisuke
K
Ohta
Masayoshi
M
Kumagai
Makiko
M
Nishi
Masakiyo
M
Hosokawa
Christian
C
Fledelius
Poul
P
Jacobsen
Hiroaki
H
Yagyu
Masashi
M
Fukayama
Ryozo
R
Nagai
Takashi
T
Kadowaki
Ken
K
Ohashi
Shun
S
Ishibashi
D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport / Q000502:physiology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism; D057057:Serine Proteases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002787:Sterol Esterase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D002352:Carrier Proteins; D002784:Cholesterol; C514712:Nceh1 protein, mouse; D002787:Sterol Esterase; D057057:Serine Proteases