Role of lysosomal acid lipase in the intracellular metabolism of LDL-transported dehydroepiandrosterone-fatty acyl esters

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Abstract

"Wang F, Wang W, Wahala K, Adlercreutz H, Ikonen E, Tikkanen MJ. Role of lysosomal acid lipase in the intracellular metabolism of LDL-transported dehydroepiandrosterone-fatty acyl esters. Am J Physiol Endocrinol Metab 295: E1455-E1461, 2008. First published September 16, 2008; doi: 10.1152/ajpendo.90527.2008. - Dehydroepiandrosterone-fatty acyl esters (DHEA-FAE) belong to a unique family of naturally occurring hydrophobic steroid hormone derivatives that are transported in circulating lipoproteins and may act as a source of dehydroepiendrosterone (DHEA) and other biologically active steroid hormones in cells. Here, we studied the metabolic fate of low-density lipoprotein-associated [H-3] DHEA-FAE ([H-3]DHEA-FAE-LDL) and the possible role of lysosomal acid lipase (LAL) in the hydrolysis of DHEA-FAE in cultured human cells. When HeLa cells were incubated with [H-3]DHEA-FAE-LDL, the accumulation of label in the cellular fraction increased with incubation time and could be inhibited by excess unlabeled LDL, suggesting LDL receptor or LDL receptor-related receptor-dependent uptake. During 48 h of chase, decreasing amounts of [H-3] DHEA-FAE were found in the cellular fraction, while in the medium increasing amounts of unesterified [H-3] DHEA and its two metabolites, [H-3]-5 alpha-androstanedione (5 alpha-adione) and [H-3] androstenedione (4- adione), appeared. As LDL-cholesteryl ester hydrolysis is dependent on LAL activity, we depleted LAL from HeLa cells using small interfering RNAs and compared the hydrolysis of [H-3]DHEA-FAE-LDL and [H-3] cholesteryl-FAE-LDL. The results demonstrated a more modest but significant reducing effect on the hydrolysis of [H-3]DHEA-FAE compared with [H-3] cholesteryl-FAE. Moreover, experiments in LAL-deficient human fibroblasts (Wolman disease patient cells) showed that [H-3]DHEA-FAE hydrolysis was not completely dependent on LAL activity. In summary, LDL-transported [H-3] DHEA-FAE entered cells via LDL receptor or LDL receptor-related receptor-mediated uptake, followed by intracellular hydrolysis and further metabolism into 5 alpha-adione and 4- adione that were excreted from cells. Although LAL contributed to the deesterification of DHEA-FAE, it was not solely responsible for the hydrolysis."
Original languageEnglish
JournalAmerican Journal of Physiology: Endocrinology and Metabolism
Volume295
Issue number6
Pages (from-to)E1455-E1461
Number of pages7
ISSN0193-1849
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3111 Biomedicine
  • 116 Chemical sciences
  • 1182 Biochemistry, cell and molecular biology

Cite this

@article{3955a8f1d0994c49a4d2718382924cbd,
title = "Role of lysosomal acid lipase in the intracellular metabolism of LDL-transported dehydroepiandrosterone-fatty acyl esters",
abstract = "{"}Wang F, Wang W, Wahala K, Adlercreutz H, Ikonen E, Tikkanen MJ. Role of lysosomal acid lipase in the intracellular metabolism of LDL-transported dehydroepiandrosterone-fatty acyl esters. Am J Physiol Endocrinol Metab 295: E1455-E1461, 2008. First published September 16, 2008; doi: 10.1152/ajpendo.90527.2008. - Dehydroepiandrosterone-fatty acyl esters (DHEA-FAE) belong to a unique family of naturally occurring hydrophobic steroid hormone derivatives that are transported in circulating lipoproteins and may act as a source of dehydroepiendrosterone (DHEA) and other biologically active steroid hormones in cells. Here, we studied the metabolic fate of low-density lipoprotein-associated [H-3] DHEA-FAE ([H-3]DHEA-FAE-LDL) and the possible role of lysosomal acid lipase (LAL) in the hydrolysis of DHEA-FAE in cultured human cells. When HeLa cells were incubated with [H-3]DHEA-FAE-LDL, the accumulation of label in the cellular fraction increased with incubation time and could be inhibited by excess unlabeled LDL, suggesting LDL receptor or LDL receptor-related receptor-dependent uptake. During 48 h of chase, decreasing amounts of [H-3] DHEA-FAE were found in the cellular fraction, while in the medium increasing amounts of unesterified [H-3] DHEA and its two metabolites, [H-3]-5 alpha-androstanedione (5 alpha-adione) and [H-3] androstenedione (4- adione), appeared. As LDL-cholesteryl ester hydrolysis is dependent on LAL activity, we depleted LAL from HeLa cells using small interfering RNAs and compared the hydrolysis of [H-3]DHEA-FAE-LDL and [H-3] cholesteryl-FAE-LDL. The results demonstrated a more modest but significant reducing effect on the hydrolysis of [H-3]DHEA-FAE compared with [H-3] cholesteryl-FAE. Moreover, experiments in LAL-deficient human fibroblasts (Wolman disease patient cells) showed that [H-3]DHEA-FAE hydrolysis was not completely dependent on LAL activity. In summary, LDL-transported [H-3] DHEA-FAE entered cells via LDL receptor or LDL receptor-related receptor-mediated uptake, followed by intracellular hydrolysis and further metabolism into 5 alpha-adione and 4- adione that were excreted from cells. Although LAL contributed to the deesterification of DHEA-FAE, it was not solely responsible for the hydrolysis.{"}",
keywords = "3111 Biomedicine, 116 Chemical sciences, 1182 Biochemistry, cell and molecular biology",
author = "Feng Wang and Wei Wang and Kristiina W{\"a}h{\"a}l{\"a} and Herman Adlercreutz and Elina Ikonen and Tikkanen, {Matti J.}",
year = "2008",
doi = "10.1152/ajpendo.90527.2008",
language = "English",
volume = "295",
pages = "E1455--E1461",
journal = "American Journal of Physiology: Endocrinology and Metabolism",
issn = "0193-1849",
publisher = "American Physiological Society",
number = "6",

}

TY - JOUR

T1 - Role of lysosomal acid lipase in the intracellular metabolism of LDL-transported dehydroepiandrosterone-fatty acyl esters

AU - Wang, Feng

AU - Wang, Wei

AU - Wähälä, Kristiina

AU - Adlercreutz, Herman

AU - Ikonen, Elina

AU - Tikkanen, Matti J.

PY - 2008

Y1 - 2008

N2 - "Wang F, Wang W, Wahala K, Adlercreutz H, Ikonen E, Tikkanen MJ. Role of lysosomal acid lipase in the intracellular metabolism of LDL-transported dehydroepiandrosterone-fatty acyl esters. Am J Physiol Endocrinol Metab 295: E1455-E1461, 2008. First published September 16, 2008; doi: 10.1152/ajpendo.90527.2008. - Dehydroepiandrosterone-fatty acyl esters (DHEA-FAE) belong to a unique family of naturally occurring hydrophobic steroid hormone derivatives that are transported in circulating lipoproteins and may act as a source of dehydroepiendrosterone (DHEA) and other biologically active steroid hormones in cells. Here, we studied the metabolic fate of low-density lipoprotein-associated [H-3] DHEA-FAE ([H-3]DHEA-FAE-LDL) and the possible role of lysosomal acid lipase (LAL) in the hydrolysis of DHEA-FAE in cultured human cells. When HeLa cells were incubated with [H-3]DHEA-FAE-LDL, the accumulation of label in the cellular fraction increased with incubation time and could be inhibited by excess unlabeled LDL, suggesting LDL receptor or LDL receptor-related receptor-dependent uptake. During 48 h of chase, decreasing amounts of [H-3] DHEA-FAE were found in the cellular fraction, while in the medium increasing amounts of unesterified [H-3] DHEA and its two metabolites, [H-3]-5 alpha-androstanedione (5 alpha-adione) and [H-3] androstenedione (4- adione), appeared. As LDL-cholesteryl ester hydrolysis is dependent on LAL activity, we depleted LAL from HeLa cells using small interfering RNAs and compared the hydrolysis of [H-3]DHEA-FAE-LDL and [H-3] cholesteryl-FAE-LDL. The results demonstrated a more modest but significant reducing effect on the hydrolysis of [H-3]DHEA-FAE compared with [H-3] cholesteryl-FAE. Moreover, experiments in LAL-deficient human fibroblasts (Wolman disease patient cells) showed that [H-3]DHEA-FAE hydrolysis was not completely dependent on LAL activity. In summary, LDL-transported [H-3] DHEA-FAE entered cells via LDL receptor or LDL receptor-related receptor-mediated uptake, followed by intracellular hydrolysis and further metabolism into 5 alpha-adione and 4- adione that were excreted from cells. Although LAL contributed to the deesterification of DHEA-FAE, it was not solely responsible for the hydrolysis."

AB - "Wang F, Wang W, Wahala K, Adlercreutz H, Ikonen E, Tikkanen MJ. Role of lysosomal acid lipase in the intracellular metabolism of LDL-transported dehydroepiandrosterone-fatty acyl esters. Am J Physiol Endocrinol Metab 295: E1455-E1461, 2008. First published September 16, 2008; doi: 10.1152/ajpendo.90527.2008. - Dehydroepiandrosterone-fatty acyl esters (DHEA-FAE) belong to a unique family of naturally occurring hydrophobic steroid hormone derivatives that are transported in circulating lipoproteins and may act as a source of dehydroepiendrosterone (DHEA) and other biologically active steroid hormones in cells. Here, we studied the metabolic fate of low-density lipoprotein-associated [H-3] DHEA-FAE ([H-3]DHEA-FAE-LDL) and the possible role of lysosomal acid lipase (LAL) in the hydrolysis of DHEA-FAE in cultured human cells. When HeLa cells were incubated with [H-3]DHEA-FAE-LDL, the accumulation of label in the cellular fraction increased with incubation time and could be inhibited by excess unlabeled LDL, suggesting LDL receptor or LDL receptor-related receptor-dependent uptake. During 48 h of chase, decreasing amounts of [H-3] DHEA-FAE were found in the cellular fraction, while in the medium increasing amounts of unesterified [H-3] DHEA and its two metabolites, [H-3]-5 alpha-androstanedione (5 alpha-adione) and [H-3] androstenedione (4- adione), appeared. As LDL-cholesteryl ester hydrolysis is dependent on LAL activity, we depleted LAL from HeLa cells using small interfering RNAs and compared the hydrolysis of [H-3]DHEA-FAE-LDL and [H-3] cholesteryl-FAE-LDL. The results demonstrated a more modest but significant reducing effect on the hydrolysis of [H-3]DHEA-FAE compared with [H-3] cholesteryl-FAE. Moreover, experiments in LAL-deficient human fibroblasts (Wolman disease patient cells) showed that [H-3]DHEA-FAE hydrolysis was not completely dependent on LAL activity. In summary, LDL-transported [H-3] DHEA-FAE entered cells via LDL receptor or LDL receptor-related receptor-mediated uptake, followed by intracellular hydrolysis and further metabolism into 5 alpha-adione and 4- adione that were excreted from cells. Although LAL contributed to the deesterification of DHEA-FAE, it was not solely responsible for the hydrolysis."

KW - 3111 Biomedicine

KW - 116 Chemical sciences

KW - 1182 Biochemistry, cell and molecular biology

U2 - 10.1152/ajpendo.90527.2008

DO - 10.1152/ajpendo.90527.2008

M3 - Article

VL - 295

SP - E1455-E1461

JO - American Journal of Physiology: Endocrinology and Metabolism

JF - American Journal of Physiology: Endocrinology and Metabolism

SN - 0193-1849

IS - 6

ER -