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Lysosomal Acid Lipase Hydrolyzes Retinyl Ester and Affects Retinoid Turnover *

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ABSTRACT

Lysosomal acid lipase (LAL) is essential for the clearance of endocytosed cholesteryl ester and triglyceride-rich chylomicron remnants. Humans and mice with defective or absent LAL activity accumulate large amounts of cholesteryl esters and triglycerides in multiple tissues. Although chylomicrons also contain retinyl esters (REs), a role of LAL in the clearance of endocytosed REs has not been reported. In this study, we found that murine LAL exhibits RE hydrolase activity. Pharmacological inhibition of LAL in the human hepatocyte cell line HepG2, incubated with chylomicrons, led to increased accumulation of REs in endosomal/lysosomal fractions. Furthermore, pharmacological inhibition or genetic ablation of LAL in murine liver largely reduced in vitro acid RE hydrolase activity. Interestingly, LAL-deficient mice exhibited increased RE content in the duodenum and jejunum but decreased RE content in the liver. Furthermore, LAL-deficient mice challenged with RE gavage exhibited largely reduced post-prandial circulating RE content, indicating that LAL is required for efficient nutritional vitamin A availability. In summary, our results indicate that LAL is the major acid RE hydrolase and required for functional retinoid homeostasis.

No MeSH data available.


LAL-deficient mice exhibit reduced RE levels in the liver. Livers of 3-month-old, ad libitum-fed LAL KO mice and WT littermates were excised, and tissue homogenates were prepared. Lipids of homogenates were extracted into hexane, and RP content was quantified by HPLC FD. RP contents were normalized to milligram of protein of homogenates and to gram of wet tissue weight and expressed as nanomoles of RE per milligram of protein (left graph) or micrograms of RE per gram of tissue (right graph), respectively. Data are presented as mean ± S.D. (n = 4 for each genotype). Statistically significant differences were determined between genotypes by Student's unpaired t test (two-tailed). *, p < 0.05; **, p < 0.01.
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Figure 5: LAL-deficient mice exhibit reduced RE levels in the liver. Livers of 3-month-old, ad libitum-fed LAL KO mice and WT littermates were excised, and tissue homogenates were prepared. Lipids of homogenates were extracted into hexane, and RP content was quantified by HPLC FD. RP contents were normalized to milligram of protein of homogenates and to gram of wet tissue weight and expressed as nanomoles of RE per milligram of protein (left graph) or micrograms of RE per gram of tissue (right graph), respectively. Data are presented as mean ± S.D. (n = 4 for each genotype). Statistically significant differences were determined between genotypes by Student's unpaired t test (two-tailed). *, p < 0.05; **, p < 0.01.

Mentions: To get first insights into the physiological role of LAL in RE turnover, we determined ROH and RE content in livers of 3-month-old WT and LAL-deficient mice. Against expectations, we found that livers of LAL-deficient mice exhibit ∼70% decreased RE content compared with that of WT littermates, irrespective of being normalized to milligram of protein of tissue homogenate (Fig. 5, left half) or to gram of tissue weight (Fig. 5, right half). Decreased retinoid content in livers of LAL-deficient mice may be caused by decreased deposition of REs in the liver because of impaired vitamin A supply.


Lysosomal Acid Lipase Hydrolyzes Retinyl Ester and Affects Retinoid Turnover *
LAL-deficient mice exhibit reduced RE levels in the liver. Livers of 3-month-old, ad libitum-fed LAL KO mice and WT littermates were excised, and tissue homogenates were prepared. Lipids of homogenates were extracted into hexane, and RP content was quantified by HPLC FD. RP contents were normalized to milligram of protein of homogenates and to gram of wet tissue weight and expressed as nanomoles of RE per milligram of protein (left graph) or micrograms of RE per gram of tissue (right graph), respectively. Data are presented as mean ± S.D. (n = 4 for each genotype). Statistically significant differences were determined between genotypes by Student's unpaired t test (two-tailed). *, p < 0.05; **, p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5016185&req=5

Figure 5: LAL-deficient mice exhibit reduced RE levels in the liver. Livers of 3-month-old, ad libitum-fed LAL KO mice and WT littermates were excised, and tissue homogenates were prepared. Lipids of homogenates were extracted into hexane, and RP content was quantified by HPLC FD. RP contents were normalized to milligram of protein of homogenates and to gram of wet tissue weight and expressed as nanomoles of RE per milligram of protein (left graph) or micrograms of RE per gram of tissue (right graph), respectively. Data are presented as mean ± S.D. (n = 4 for each genotype). Statistically significant differences were determined between genotypes by Student's unpaired t test (two-tailed). *, p < 0.05; **, p < 0.01.
Mentions: To get first insights into the physiological role of LAL in RE turnover, we determined ROH and RE content in livers of 3-month-old WT and LAL-deficient mice. Against expectations, we found that livers of LAL-deficient mice exhibit ∼70% decreased RE content compared with that of WT littermates, irrespective of being normalized to milligram of protein of tissue homogenate (Fig. 5, left half) or to gram of tissue weight (Fig. 5, right half). Decreased retinoid content in livers of LAL-deficient mice may be caused by decreased deposition of REs in the liver because of impaired vitamin A supply.

View Article: PubMed Central - PubMed

ABSTRACT

Lysosomal acid lipase (LAL) is essential for the clearance of endocytosed cholesteryl ester and triglyceride-rich chylomicron remnants. Humans and mice with defective or absent LAL activity accumulate large amounts of cholesteryl esters and triglycerides in multiple tissues. Although chylomicrons also contain retinyl esters (REs), a role of LAL in the clearance of endocytosed REs has not been reported. In this study, we found that murine LAL exhibits RE hydrolase activity. Pharmacological inhibition of LAL in the human hepatocyte cell line HepG2, incubated with chylomicrons, led to increased accumulation of REs in endosomal/lysosomal fractions. Furthermore, pharmacological inhibition or genetic ablation of LAL in murine liver largely reduced in vitro acid RE hydrolase activity. Interestingly, LAL-deficient mice exhibited increased RE content in the duodenum and jejunum but decreased RE content in the liver. Furthermore, LAL-deficient mice challenged with RE gavage exhibited largely reduced post-prandial circulating RE content, indicating that LAL is required for efficient nutritional vitamin A availability. In summary, our results indicate that LAL is the major acid RE hydrolase and required for functional retinoid homeostasis.

No MeSH data available.