Steroid hormones are synthesized using cholesterol as precursor, with a substantial portion supplied by the selective uptake of lipoprotein-derived cholesteryl esters. Adrenals express a high level of neutral cholesteryl ester hydrolase activity, and recently hormone-sensitive lipase (HSL) was shown to be responsible for most adrenal neutral cholesteryl ester hydrolase activity. To determine the functional importance of HSL in adrenal steroidogenesis, adrenal cells were isolated from control and HSL-/- mice, and the in vitro production of corticosterone was quantified. Results show that, even though adrenal cholesteryl ester content was substantially elevated in both male and female HSL-/- mice, basal corticosterone production was reduced approximately 50%. The maximum corticosterone production induced by dibutyryl cAMP, and lipoproteins was approximately 75-85% lower in adrenal cells from HSL-/- mice compared with control. There is no intrinsic defect in the conversion of cholesterol into steroids in HSL-/- mice. Dibutyryl cAMP-stimulated conversion of high-density lipoprotein cholesteryl esters into corticosterone was reduced 97% in HSL-/- mice. An increase in low-density lipoprotein receptor expression appears to be one of the compensatory mechanisms for cholesterol delivery in HSL-/- mice. These findings suggest that HSL is functionally linked to the selective pathway and is critically involved in the intracellular processing and availability of cholesterol for adrenal steroidogenesis.
1,25 dihydroxy vitamin D (calcitriol); 1,25(OH)(2)D; 18kDa translocator protein; 3-hydroxy-3-methylglutaryl co-enzyme A; 3β-hydroxysteroid dehydrogenase; 3βHSD; ACAT; ACTH; ANT; CRAC; Cholesterol side chain cleavage; Cholesterol transport; ER; FAD; HDL; HMGCoA; HSL; IMM; IMS; Km; LAL; LDL; LH; MENTAL; MENTHO; MLN64; MLN64 N-terminal; MLN64 N-terminal domain homologue; Michaelis constant; NADPH; NPC; Niemann Pick type C; OMM; Outer mitochondrial membrane; P450scc; PAP7; PBR; PCP; PKA; PKAR1A; PRAX1; PTH; SF1; SOAT; SR-B1; SREBPs; START; StAR; StAR-related lipid transfer domain; Steroidogenesis; Steroidogenic acute regulatory protein; TSPO; TSPO-associated protein 1; TSPO-associated protein 7 (ACBD3); VDAC1; Vitamin D; acyl transferase; adenine nucleotide transporter; adrenocorticotropic hormone; cholesterol recognition amino acid consensus domain; endoplasmic reticulum; flavin adenine dinucleotide; high density lipoproteis; hormone-sensitive neutral lipase; inner mitochondrial membrane; intramembranous space; low-density lipoproteins; luteinizing hormone; lysosomal acid lipase; metastatic lymph node clone 64; mitochondrial cytochrome P450 specific for cholesterol side-chain cleavage; nicotinamide adenine dinucleotide phosphate; outer mitochondrial membrane; parathyroid hormone; peripheral benzodiazepine receptor; phosphate carrier protein; protein kinase A; protein kinase A regulatory subunit 1α; scavenger receptor B1; steroidogenic acute regulatory protein; steroidogenic factor 1; sterol O-acetyltransferase; sterol regulatory element binding proteins; voltage-dependent anion channel