Submitted on February 1, 2008
Revised on July 22, 2008
Accepted on July 22, 2008
Disturbed cholesterol homeostasis in hormone-sensitive lipase null mice
Celine Fernandez1*, Marie Lindholm1, Morten Krogh1, Stéphanie Lucas1, Sara Larsson1, Peter Osmark1, Karin Berger1, Jan Boren2, Barbara A Fielding3, Keith N. Frayn3, and Cecilia Holm1
1 Lund University
2 The Sahlgrenska Academy at Göteborg University
3 University of Oxford
* To whom correspondence should be addressed. E-mail: Celine.Fernandez{at}med.lu.se.
Transcriptomics analysis revealed that genes involved in hepatic de novo cholesterol synthesis were down-regulated in fed HSL-null mice that had been on high-fat diet (HFD) for 6 months. This finding prompted a further analysis of cholesterol metabolism in HSL-null mice, which was performed in fed and 16-h fasted mice on a normal chow diet (ND) or a HFD regimen. Plasma cholesterol was elevated in HSL-null mice, in all tested conditions, as a result of cholesterol enrichment of HDL and VLDL. Hepatic esterified cholesterol content and ATP binding cassette transporter A1 (ABCA1) mRNA and protein levels were increased in HSL-null mice regardless of the dietary regimen. Unsaturated fatty acid composition of hepatic triglycerides was modified in fasted HSL-null mice on ND and HFD. The increased ABCA1 expression had no major effect on cholesterol efflux from HSL-null mouse hepatocytes. Taken together, the results of this study suggest that HSL plays a critical role in the hydrolysis of cytosolic cholesteryl esters and that increased levels of hepatic cholesteryl esters, due to lack of action of HSL in the liver, is the main mechanism underlying the imbalance in cholesterol metabolism in HSL-null mice.
