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StAR Overexpression Decreases Serum and Tissue Lipids in Apolipoprotein E-deficient Mice

  • Original Article
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Lipids

Abstract

Cholesterol metabolism as initiated by mitochondrial sterol 27-hydroxylase (CYP27A1) is a ubiquitous pathway capable of synthesizing multiple key regulatory oxysterols involved in lipid homeostasis. Previously we have shown that the regulation of its activities within hepatocytes is highly controlled by the rate of mitochondrial cholesterol delivery. In the present study, we hypothesized that increasing expression of the mitochondrial cholesterol delivery protein, steroidogenic acute regulatory protein (StAR), is able to lower lipid accumulation in liver, aortic wall, as well as in serum in a well-documented animal model, apolipoprotein E-deficient (apoE−/−) mice. ApoE−/− mice, characterized by increased serum, liver, and endothelial cholesterol and triglyceride levels by 3 months of age, were infected with recombinant cytomegalovirus (CMV)-StAR adenovirus to increase StAR protein expression. Six days following infection, serum total cholesterol and triglycerides had decreased 19 and 30% (P < 0.01), respectively, with a compensatory 40% (P < 0.01) increase in serum HDL-cholesterol in increased StAR expressing mice as compared to controls (no or control virus). Histologic and biochemical analysis of the liver demonstrated not only a dramatic decrease in cholesterol (↓25%; P < 0.01), but an even more marked decrease in triglyceride (↓56%; P < 0.01) content. En bloc Sudan IV staining of the aorta revealed a >80% (P < 0.01) decrease in neutral lipid staining. This study demonstrates for the first time a possible therapeutic role of the CYP27A1-initiated pathway in the treatment of dyslipidemias.

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Abbreviations

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

apoE−/− :

Apolipoprotein E-deficient

AST:

Aspartate aminotransferase

BAS:

Bile acid synthesis

CMV:

Cytomegalovirus

CTX:

Cerebrotendinous xanthomatosis

CYP7A1:

Cholesterol 7 alpha-hydroxylase

CYP27A1:

Sterol 27-hydroxylase

EGFP:

Enhanced Green fluorescent protein

HDL:

High density lipoprotein

HDL-CHO:

HDL cholesterol

IDL:

Intermediate-density lipoproteins

LDL:

Low density lipoprotein

NS:

Normal saline

O.C.T:

Optimum cutting temperature compound

PC-TP:

Phosphatidylcholine transfer protein

PPARγ:

Proliferation peroxysome activator receptor gamma

StAR:

Steroidogenic acute regulatory protein

START:

StAR-related lipid transfer domain

T-CHO:

Total cholesterol

TG:

Triglyceride

VLDL:

Very low-density lipoproteins

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (30871021) of the People’s Republic of China (Yin, L), and the United States National Institutes of Health R01HL078898 (Ren, S).

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Authors and Affiliations

  1. Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, PO Box 224, 138 Yixueyuan Road, 200032, Shanghai, People’s Republic China

    Yanxia Ning, Leyuan Xu, Sifeng Chen & Lianhua Yin

  2. Department of Medicine, Veterans Affairs Medical Center and Virginia Commonwealth University, Richmond, VA, USA

    Shunlin Ren & William M. Pandak

Authors
  1. Yanxia Ning
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  2. Leyuan Xu
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  3. Shunlin Ren
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  4. William M. Pandak
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  5. Sifeng Chen
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  6. Lianhua Yin
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Corresponding authors

Correspondence to Sifeng Chen or Lianhua Yin.

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Ning, Y., Xu, L., Ren, S. et al. StAR Overexpression Decreases Serum and Tissue Lipids in Apolipoprotein E-deficient Mice. Lipids 44, 511–519 (2009). https://doi.org/10.1007/s11745-009-3299-1

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  • DOI: https://doi.org/10.1007/s11745-009-3299-1

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