Adenovirus-mediated transfer of a gene encoding cholesterol 7α-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol

David K. Spady, Jennifer A. Cuthbert, Maureen N. Willard, Robert S. Meidell

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Clinical interventions that accelerate conversion of cholesterol to bile acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations. The initial and rate-limiting step in the bile acid biosynthetic pathway is catalyzed by hepatic cholesterol 7α-hydroxylase. To examine the effects of transient primary overexpression of this enzyme on sterol metabolism and lipoprotein transport, we constructed a recombinant adenovirus in which a cDNA encoding rat 7α-hydroxylase is expressed from the human cytomegalovirus immediate-early promoter (AdCMVTα). Syrian hamsters administered AdCMVTα intravenously accumulated transgene-specific mRNA in the liver and demonstrated a dose-dependent increase in hepatic microsomal 7α-hydroxylase activity. The increased conversion of cholesterol to bile acids resulted in a compensatory increase in hepatic cholesterol synthesis. In addition, overexpression of 7α-hydroxylase reduced the rate of LDL cholesterol entry into the plasma space and, in animals maintained on a Western-type diet, restored hepatic LDL receptor expression. As a consequence, plasma LDL concentrations fell by -60% in animals maintained on control diet and by -75% in animals consuming a Western-type diet. Plasma high density lipoprotein cholesterol levels were reduced to a lesser degree. These results demonstrate that transient upregulation of bile acid synthesis by direct transfer of a 7α-hydroxylase gene favorably alters circulating lipoprotein profiles and suggest one potential molecular target for genetic strategies aimed at reducing cardiovascular risk.

Original languageEnglish (US)
Pages (from-to)700-709
Number of pages10
JournalJournal of Clinical Investigation
Volume96
Issue number2
StatePublished - Aug 1995

Fingerprint

Cholesterol 7-alpha-Hydroxylase
Adenoviridae
Cricetinae
LDL Cholesterol
Mixed Function Oxygenases
Bile Acids and Salts
Liver
Enzymes
Genes
Cholesterol
Lipoproteins
LDL Receptors
Biosynthetic Pathways
Mesocricetus
Sterols
Cytomegalovirus
Transgenes
LDL Lipoproteins
HDL Cholesterol
Molecular Biology

Keywords

  • Bile acids
  • Cholesterol
  • Genes
  • Lipoprotein
  • Viruses

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{b74ad291b6d64bd5b790cb726ed98eba,
title = "Adenovirus-mediated transfer of a gene encoding cholesterol 7α-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol",
abstract = "Clinical interventions that accelerate conversion of cholesterol to bile acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations. The initial and rate-limiting step in the bile acid biosynthetic pathway is catalyzed by hepatic cholesterol 7α-hydroxylase. To examine the effects of transient primary overexpression of this enzyme on sterol metabolism and lipoprotein transport, we constructed a recombinant adenovirus in which a cDNA encoding rat 7α-hydroxylase is expressed from the human cytomegalovirus immediate-early promoter (AdCMVTα). Syrian hamsters administered AdCMVTα intravenously accumulated transgene-specific mRNA in the liver and demonstrated a dose-dependent increase in hepatic microsomal 7α-hydroxylase activity. The increased conversion of cholesterol to bile acids resulted in a compensatory increase in hepatic cholesterol synthesis. In addition, overexpression of 7α-hydroxylase reduced the rate of LDL cholesterol entry into the plasma space and, in animals maintained on a Western-type diet, restored hepatic LDL receptor expression. As a consequence, plasma LDL concentrations fell by -60{\%} in animals maintained on control diet and by -75{\%} in animals consuming a Western-type diet. Plasma high density lipoprotein cholesterol levels were reduced to a lesser degree. These results demonstrate that transient upregulation of bile acid synthesis by direct transfer of a 7α-hydroxylase gene favorably alters circulating lipoprotein profiles and suggest one potential molecular target for genetic strategies aimed at reducing cardiovascular risk.",
keywords = "Bile acids, Cholesterol, Genes, Lipoprotein, Viruses",
author = "Spady, {David K.} and Cuthbert, {Jennifer A.} and Willard, {Maureen N.} and Meidell, {Robert S.}",
year = "1995",
month = "8",
language = "English (US)",
volume = "96",
pages = "700--709",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",

}

TY - JOUR

T1 - Adenovirus-mediated transfer of a gene encoding cholesterol 7α-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol

AU - Spady, David K.

AU - Cuthbert, Jennifer A.

AU - Willard, Maureen N.

AU - Meidell, Robert S.

PY - 1995/8

Y1 - 1995/8

N2 - Clinical interventions that accelerate conversion of cholesterol to bile acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations. The initial and rate-limiting step in the bile acid biosynthetic pathway is catalyzed by hepatic cholesterol 7α-hydroxylase. To examine the effects of transient primary overexpression of this enzyme on sterol metabolism and lipoprotein transport, we constructed a recombinant adenovirus in which a cDNA encoding rat 7α-hydroxylase is expressed from the human cytomegalovirus immediate-early promoter (AdCMVTα). Syrian hamsters administered AdCMVTα intravenously accumulated transgene-specific mRNA in the liver and demonstrated a dose-dependent increase in hepatic microsomal 7α-hydroxylase activity. The increased conversion of cholesterol to bile acids resulted in a compensatory increase in hepatic cholesterol synthesis. In addition, overexpression of 7α-hydroxylase reduced the rate of LDL cholesterol entry into the plasma space and, in animals maintained on a Western-type diet, restored hepatic LDL receptor expression. As a consequence, plasma LDL concentrations fell by -60% in animals maintained on control diet and by -75% in animals consuming a Western-type diet. Plasma high density lipoprotein cholesterol levels were reduced to a lesser degree. These results demonstrate that transient upregulation of bile acid synthesis by direct transfer of a 7α-hydroxylase gene favorably alters circulating lipoprotein profiles and suggest one potential molecular target for genetic strategies aimed at reducing cardiovascular risk.

AB - Clinical interventions that accelerate conversion of cholesterol to bile acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations. The initial and rate-limiting step in the bile acid biosynthetic pathway is catalyzed by hepatic cholesterol 7α-hydroxylase. To examine the effects of transient primary overexpression of this enzyme on sterol metabolism and lipoprotein transport, we constructed a recombinant adenovirus in which a cDNA encoding rat 7α-hydroxylase is expressed from the human cytomegalovirus immediate-early promoter (AdCMVTα). Syrian hamsters administered AdCMVTα intravenously accumulated transgene-specific mRNA in the liver and demonstrated a dose-dependent increase in hepatic microsomal 7α-hydroxylase activity. The increased conversion of cholesterol to bile acids resulted in a compensatory increase in hepatic cholesterol synthesis. In addition, overexpression of 7α-hydroxylase reduced the rate of LDL cholesterol entry into the plasma space and, in animals maintained on a Western-type diet, restored hepatic LDL receptor expression. As a consequence, plasma LDL concentrations fell by -60% in animals maintained on control diet and by -75% in animals consuming a Western-type diet. Plasma high density lipoprotein cholesterol levels were reduced to a lesser degree. These results demonstrate that transient upregulation of bile acid synthesis by direct transfer of a 7α-hydroxylase gene favorably alters circulating lipoprotein profiles and suggest one potential molecular target for genetic strategies aimed at reducing cardiovascular risk.

KW - Bile acids

KW - Cholesterol

KW - Genes

KW - Lipoprotein

KW - Viruses

UR - http://www.scopus.com/inward/record.url?scp=0029160030&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029160030&partnerID=8YFLogxK

M3 - Article

VL - 96

SP - 700

EP - 709

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 2

ER -