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Congenital Lipoid Adrenal Hyperplasia

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Cholesterol Transporters of the START Domain Protein Family in Health and Disease

Abstract

All steroid hormones are made from cholesterol, which is primarily taken up by steroidogenic cells from circulating lipoproteins. The intracellular mechanisms by which cholesterol is delivered to cellular destinations remains under investigation. Steroidogenic cells must transport large amounts of cholesterol to, and then into, the mitochondria, where the cholesterol side-chain cleavage enzyme, P450scc, resides. P450scc is the first enzyme in steroidogenesis, converting insoluble cholesterol to soluble pregnenolone. The combination of genetic studies of a rare disease, congenital lipoid adrenal hyperplasia (lipoid CAH), and studies of the cell biology of mitochondrial cholesterol import led to the discovery of the steroidogenic acute regulatory protein (StAR). StAR acts exclusively on the outer mitochondrial membrane to trigger mitochondrial cholesterol import, but the precise mechanism of its action remains unclear. Lipoid CAH is caused by StAR mutations and is thus the StAR knockout experiment of nature. Recent work has shown that P450scc mutations cause a disease that is a phenocopy of lipoid CAH. The discovery of StAR led to the discovery of the broader family of structurally related StAR-related lipid transfer (START)-domain proteins. It appears that some of these START proteins may also be involved in intracellular cholesterol trafficking upstream from StAR.

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Abbreviations

3βHSD:

3β-hydroxysteroid dehydrogenase

ACAT:

acyl-coenzyme A cholesteroacyl transferase

ACTH:

adrenocorticotropic hormone

ANT:

adenine nucleotide

CRAC:

cholesterol recognition amino acid consensus domain

ER:

endoplasmic reticulum

FAD:

flavin adenine dinucleotide

HDL:

high density lipoproteins

HSL:

hormone-sensitive neutral lipase

HMGCoA:

3-hydroxy-3-methylglutaryl co-enzyme A

IMM:

inner mitochondrial membrane

IMS:

intramembranous space

Km:

Michaelis constant

LAL:

lysosomal acid lipase

LDL:

low-density lipoproteins

LH:

luteinizing hormone

MENTAL:

MLN64 N-terminal

MENTHO:

MLN64 N-terminal domain homologue

MLN64:

metastatic lymph node clone 64

NADPH:

nicotinamide adenine dinucleotide phosphate

NPC:

Niemann-Pick type C

OMM:

outer mitochondrial membrane

PAP7:

TSPO-associated protein 7 (ACBD3)

PBR:

peripheral benzodiazepine receptor

PCP:

phosphate carrier protein

PKA:

protein kinase A

PKAR1A:

protein kinase A regulatory subunit 1α

PRAX1:

TSPO-associated protein 1

P450scc:

mitochondrial cytochrome P450 specific for cholesterol side-chain cleavage

SF1:

steroidogenic factor 1

SOAT:

sterol O-acetyltransferase

SR-B1:

scavenger receptor B1

StAR:

steroidogenic acute regulatory protein

START:

StAR-related lipid transfer domain

SREBPs:

sterol regulatory element binding proteins

TSPO:

18 kDa translocator protein,

VDAC1:

voltage-dependent anion channel

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  1. Department of Pediatrics, University of California San Francisco, 94143-1346, San Francisco, CA, USA

    Prof. Walter L. Miller M.D.

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  1. Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky, USA

    Barbara J. Clark

  2. Cell Biology and Biochemistry, Texas Tech Univ. Health Sciences Center, Lubbock, Texas, USA

    Douglas M. Stocco

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Miller, W. (2014). Congenital Lipoid Adrenal Hyperplasia. In: Clark, B., Stocco, D. (eds) Cholesterol Transporters of the START Domain Protein Family in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1112-7_4

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