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Mitochondrial cholesterol transport: A possible target in the management of hyperlipidemia

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Lipids

Abstract

Sterol 27-hydroxylase (CYP27A1) may defend cells against accumulation of excess cholesterol, making this enzyme a possible target in the management of hyperlipidemia. The study objective was to analyze cholesterol homeostatic responses to increases in CYP27A1 activity in HepG2 cells and primary human hepatocytes. Increasing CYP27A1 activity by increasing enzyme expression led to significant increases in bile acid synthesis with compensatory increases in HMG-CoA reductase (HMGR) activity/protein, LDL receptor (LDLR) mRNA, and LDLR-mediated cholesterol uptake. Under these conditions, only a small increase in cellular 27-hydroxycholesterol (27OH-Chol) concentration was observed. No changes were detected in mature sterol regulatory element-binding proteins (SREBP) 1 or 2. Increasing CYP27A1 activity by increasing mitochondrial cholesterol transport (i.e., substrate availability) led to greater increases in bile acid synthesis with significant increases in cellular 27OH-Chol concentration. Mature SREBP 2 protein decreased significantly with compensatory decreases in HMGR protein. No change was detected in mature SREBP 1 protein. Despite increasing 27OH-Chol and lowering SREBP 2 protein concentrations, LDLR mRNA increased significantly, suggesting alternative mechanisms of LDLR transcriptional regulation. These findings suggest that regulation of liver mitochondrial cholesterol transport represents a potential therapeutic strategy in the treatment of hyperlipidemia and atherosclerosis.

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Abbreviations

27OH-Chol:

27-hydroxycholesterol, cholesten-5-ene-3β,25R(26)-diol

ATCC:

American Type Culture Collection

Chol:

cholesterol

CTX:

cerebrotendinous xanthomatosis

CYP7B1:

oxysterol 7α hydroxylase

CYP27A1:

sterol 27-hydroxylase

DiI:

1,1′-dioctadecyl-3,3,3′,3′-tetramethyl-indocarbocyanine perchlorate

ECL:

enhanced chemiluminescence

HMGR:

HMG-CoA reductase

HRP:

horseradish peroxidase

LDLR:

LDL-receptor

LPDS:

lipoprotein-deficient serum

SR-B1:

HDL-receptor

SREBP:

sterol regulatory element-binding protein

StAR:

steroidogenic acute regulatory protein

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Authors and Affiliations

  1. Department of Internal Medicine, Virginia Commonwealth University, 1201 Broad Rock Blvd., 23249, Richmond, VA

    E. A. Hall, S. Ren & W. M. Pandak

  2. Department of Microbiology and Immunology, Virginia Commonwealth University, 1201 Broad Rock Blvd., 23249, Richmond, VA

    P. B. Hylemon

  3. Department of Biochemistry, Virginia Commonwealth University, 1201 Broad Rock Blvd., 23249, Richmond, VA

    A. del Castillo & G. Gil

  4. Department of Internal Medicine, McGuire Veterans Affairs Medical Center, 1201 Broad Rock Blvd., 23249, Richmond, VA

    S. Ren, K. Redford & W. M. Pandak

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  1. E. A. Hall
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  2. S. Ren
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  3. P. B. Hylemon
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  5. A. del Castillo
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  6. G. Gil
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  7. W. M. Pandak
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Correspondence to W. M. Pandak.

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Hall, E.A., Ren, S., Hylemon, P.B. et al. Mitochondrial cholesterol transport: A possible target in the management of hyperlipidemia. Lipids 40, 1237–1244 (2005). https://doi.org/10.1007/s11745-005-1491-0

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  • DOI: https://doi.org/10.1007/s11745-005-1491-0

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