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,Mitsuyo Okazaki,Takanari Gotoda,Ryozo Nagai,Takashi Kadowaki,Hitoshi Shimano,Nobuhiro Yamada,Shun Ishibashi

doi:10.1194/jlr.m800198-jlr200

Abstract

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 (Lep(ob/ob)/HSL(-/-)) showed massive accumulation of CE in the liver compared with Lep(ob/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.

Highlights

Hormone-sensitive lipase (HSL) regulates the hydrolysis of acylglycerol and cholesteryl ester (CE) in various organs, including adipose tissues
To determine the effect of HSL deficiency on hepatic lipid metabolism, especially in a leptin-deficient obesity model, HSL2/2 mice were cross-bred with leptin-deficient Lepob/ob mice and the liver lipid content of each genotype was measured (6 h fasted mice; Fig. 1A)
We show here that HSL was expressed in hepatocytes and that a deficiency of HSL induced hepatic CE accumulation, especially under two different nutritional conditions: leptin deficiency and dietary cholesterol load

Summary

Introduction

Hormone-sensitive lipase (HSL) regulates the hydrolysis of acylglycerol and cholesteryl ester (CE) in various organs, including adipose tissues. Feeding diets containing high cholesterol resulted in the accumulation of hepatic CEs in HSL2/2 mice. Both leptin deficiency and dietary cholesterol load induce massive accumulation of CEs in the liver of HSL2/2 mice

Results

Conclusion