Abstract
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl ester (CE) and retinyl ester (RE) and triglyceride (TG). Mice globally lacking LAL accumulate CE most prominently in the liver. The severity of the CE accumulation phenotype progresses with age and is accompanied by hepatomegaly and hepatic cholesterol crystal deposition. In contrast, hepatic TG accumulation is much less pronounced in these mice, and hepatic RE levels are even decreased. To dissect the functional role of LAL for neutral lipid ester mobilization in the liver, we generated mice specifically lacking LAL in hepatocytes (hep-LAL-ko). On a standard chow diet, hep-LAL-ko mice exhibited increased hepatic CE accumulation but unaltered TG and RE levels. Feeding the hep-LAL-ko mice a vitamin A excess/high-fat diet (VitA/HFD) further increased hepatic cholesterol levels, but hepatic TG and RE levels in these mice were lower than in control mice. Performing in vitro activity assays with lysosome-enriched fractions from livers of mice globally lacking LAL, we detected residual acid hydrolytic activities against TG and RE. Interestingly, this non-LAL acid TG hydrolytic activity was elevated in lysosome-enriched fractions from livers of hep-LAL-ko mice upon VitA/HFD feeding. In conclusion, the neutral lipid ester phenotype in livers from hep-LAL-ko mice indicates that LAL is limiting for CE turnover, but not for TG and RE turnovers. Furthermore, in vitro hydrolase activity assays revealed the existence of non-LAL acid hydrolytic activities for TG and RE. The corresponding acid lipase(s) catalyzing these reactions remains to be identified.
Highlights
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl ester (CE) and retinyl ester (RE) and triglyceride (TG)
Offspring carrying the floxed Lipa allele were crossed with mice expressing Cre recombinase under the control of the albumin promoter, which resulted in mice lacking LAL expression in hepatocytes
Purities of the cell preparations were confirmed by high-mRNA expression levels of the hepatocyte markers glucose-6-phosphatase (G6Pase) and glycerol kinase (GK) in hepatocytes and high mRNA expression of the endothelial cell marker CD31 as well as macrophage marker F4/80 in nonparenchymal cells (NPCs) (Fig. 1B)
Summary
LAL-ko mice show increased hepatic expression of genes involved in fatty acid (FA) and cholesterol (CHOL) biosynthesis [8] These changes in hepatic lipid homeostasis are likely a compensatory mechanism for the lysosomal lipid/CHOL entrapment, further aggravating the lipid accumulation phenotype with age [8]. It is puzzling that LAL-ko mice exhibit decreased hepatic RE content, recombinant LAL has been shown to hydrolyze retinyl palmitate (RP), and liver homogenates of LAL-ko mice show 90% lower acid RE hydrolase activity [9, 10]. Lysosome-enriched fractions of liver from hep-LAL-ko mice on VitA/HFD contained increased acid TG hydrolase activities, which were not inhibited by the presence of the LAL-specific inhibitor Lalistat 2, suggesting the presence of so-far uncharacterized acid lipase(s)
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