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Originally published In Press as doi:10.1194/jlr.M800198-JLR200 on May 14, 2008

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Journal of Lipid Research, Vol. 49, 1829-1838, August 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Hormone-sensitive lipase is involved in hepatic cholesteryl ester hydrolysis

Motohiro Sekiya*, Jun-ichi Osuga*, Naoya Yahagi*, Hiroaki Okazaki*, Yoshiaki Tamura*, Masaki Igarashi*, Satoru Takase*, Kenji Harada*, Sachiko Okazaki*, Yoko Iizuka*, Ken Ohashi*, Hiroaki Yagyu{dagger}, Mitsuyo Okazaki§, Takanari Gotoda*, Ryozo Nagai**, Takashi Kadowaki*, Hitoshi Shimano{dagger}{dagger}, Nobuhiro Yamada{dagger}{dagger} and Shun Ishibashi1,*,{dagger}

* Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
** Department of Cardiovascular Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
§ Laboratory of Chemistry, Department of General Education, Tokyo Medical and Dental University, Chiba 272-0827, Japan
{dagger}{dagger} Department of Metabolism, Endocrinology, and Atherosclerosis, Institute of Clinical Medicine, University of Tsukuba, Ibaragi 305-8575, Japan
{dagger} Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan

This work was partially supported by Grants-in-Aid from the Japan Health Science Foundation and by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists (to M.S.). This work was also supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture and by the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation.

Published, JLR Papers in Press, May 9, 2008.

1 To whom correspondence should be addressed. e-mail: ishibash{at}jichi.ac.jp

Hormone-sensitive lipase (HSL) regulates the hydrolysis of acylglycerol and cholesteryl ester (CE) in various organs, including adipose tissues. However, the hepatic expression level of HSL has been reported to be almost negligible. In the present study, we found that mice lacking both leptin and HSL (Lepob/ob/HSL–/–) showed massive accumulation of CE in the liver compared with Lepob/ob/HSL+/+ mice, while triacylglycerol (TG) accumulation was modest. Similarly, feeding with a high-cholesterol diet induced hepatic CE accumulation in HSL–/– mice. Supporting these observations, we detected significant expression of protein as well as mRNA of HSL in the liver. HSL–/– mice showed reduced activity of CE hydrolase, but not of TG lipase, in the liver compared with wild-type mice. Furthermore, we confirmed the expression of HSL in viable parenchymal cells isolated from wild-type mice. The hepatocytes from HSL–/– mice showed reduced activity of CE hydrolase and contained more CE than those from HSL+/+ mice even without the incubation with lipoproteins. Incubation with LDL further augmented the accumulation of CE in the HSL-deficient hepatocytes. From these results, we conclude that HSL is involved in the hydrolysis of CE in hepatocyes.

Supplementary key words fatty liver • leptin • mouse • lipoproteins • ob/ob • hepatocytes

Abbreviations: ALT, alanine aminotransferase; ATGL, adipose triglyceride lipase; CE, cholesteryl ester; CEL, carboxyl ester lipase; DG, diacylglycerol; HSL, hormone-sensitive lipase; LAL, lysosomal acid lipase; LPDS, lipoprotein-deficient serum; NPC, nonparenchymal cell; PC, parenchymal cell; SREBP, sterol-regulatory element binding protein; TG, triacylglycerol


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