Disturbed cholesterol homeostasis in hormone-sensitive lipase-null mice.
Transcriptomics analysis revealed that genes involved in hepatic de novo cholesterol synthesis were downregulated in fed HSL-null mice that had been on a high-fat diet (HFD) for 6 mo. 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 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, are the main mechanism underlying the imbalance in cholesterol metabolism in HSL-null mice.
Fernandez
Céline
C
Department of Experimental Medical Science, Lund University, BMC C11, SE-221 84 Lund, Sweden. celine.fernandez@med.lu.se
Lindholm
Marie
M
Krogh
Morten
M
Lucas
Stéphanie
S
Larsson
Sara
S
Osmark
Peter
P
Berger
Karin
K
Borén
Jan
J
Fielding
Barbara
B
Frayn
Keith
K
Holm
Cecilia
C
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002787:Sterol Esterase / Q000235:genetics* / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D005227:Fatty Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol; D002787:Sterol Esterase