J. Lipid Res.
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A more recent version of this article appeared on August 1, 2008

Papers In Press, published online ahead of print May 14, 2008
J. Lipid Res., doi:10.1194/jlr.M800198-JLR200
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Submitted on April 22, 2008
Revised on May 9, 2008
Accepted on May 9, 2008

Hormone-sensitive lipase is involved in hepatic cholesterol 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, Michiyo Okazaki, Takanari Gotoda, Ryozo Nagai, Takashi Kadowaki, Hitoshi Shimano, Nobuhiro Yamada, and Shun Ishibashi

Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498

Corresponding Author: ishibash{at}jichi.ac.jp

Hormone-sensitive lipase (HSL) regulates the hydrolysis of acylglycerol and cholesterol ester (CE) in various organs including adipose tissues. However, 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 triglyceride (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.


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