Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element-binding proteins

Jih Tung Pai, Oleg Guryev, Michael S. Brown, Joseph L. Goldstein

Research output: Contribution to journalArticle

181 Citations (Scopus)

Abstract

Three sterol regulatory element-binding proteins (SREBP-1a, -1c, and - 2) stimulate transcription of genes involved in synthesis and receptor- mediated uptake of cholesterol and fatty acids. Here, we explore the individual roles of each SREBP by preparing lines of Chinese hamster ovary (CHO) cells that express graded amounts of nuclear forms of each SREBP (designated nSREBPs) under control of a muristerone-inducible nuclear receptor system. The parental hamster cell line (M19 cells) lacks its own nSREBPs, owing to a deletion in the gene encoding the Site-2 protease, which releases nSREBPs from cell membranes. By varying the concentration of muristerone, we obtained graded expression of individual nSREBPs in the range that restored lipid synthesis to near physiologic levels. The results show that nSREBP-2 produces a higher ratio of synthesis of cholesterol over fatty acids than does nSREBP-1a. This is due in part to a selective ability of low levels of nSREBP-2, but not nSREBP-1a, to activate the promoter for squalene synthase. nSREBP-1a and -2 both activate transcription of the genes encoding stearoyl-CoA desaturase-1 and -2, thereby markedly enhancing the production of monounsaturated fatty acids. nSREBP-1c was inactive in stimulating any transcription at the concentrations achieved in these studies. The current data support the emerging view that the nSREBPs act in complementary ways to modulate the lipid composition of cell membranes.

Original languageEnglish (US)
Pages (from-to)26138-26148
Number of pages11
JournalJournal of Biological Chemistry
Volume273
Issue number40
DOIs
StatePublished - Oct 2 1998

Fingerprint

Sterol Regulatory Element Binding Proteins
Sterol Regulatory Element Binding Protein 1
Biosynthesis
Transcription
Unsaturated Fatty Acids
Gene encoding
Cholesterol
Cells
Cell membranes
Fatty Acids
Farnesyl-Diphosphate Farnesyltransferase
Stearoyl-CoA Desaturase
Lipids
Monounsaturated Fatty Acids
Gene Deletion
Membrane Lipids
Cytoplasmic and Nuclear Receptors
Cricetulus
Cricetinae
Genes

ASJC Scopus subject areas

  • Biochemistry

Cite this

@article{76b02e0e542443988dc5c272036a2589,
title = "Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element-binding proteins",
abstract = "Three sterol regulatory element-binding proteins (SREBP-1a, -1c, and - 2) stimulate transcription of genes involved in synthesis and receptor- mediated uptake of cholesterol and fatty acids. Here, we explore the individual roles of each SREBP by preparing lines of Chinese hamster ovary (CHO) cells that express graded amounts of nuclear forms of each SREBP (designated nSREBPs) under control of a muristerone-inducible nuclear receptor system. The parental hamster cell line (M19 cells) lacks its own nSREBPs, owing to a deletion in the gene encoding the Site-2 protease, which releases nSREBPs from cell membranes. By varying the concentration of muristerone, we obtained graded expression of individual nSREBPs in the range that restored lipid synthesis to near physiologic levels. The results show that nSREBP-2 produces a higher ratio of synthesis of cholesterol over fatty acids than does nSREBP-1a. This is due in part to a selective ability of low levels of nSREBP-2, but not nSREBP-1a, to activate the promoter for squalene synthase. nSREBP-1a and -2 both activate transcription of the genes encoding stearoyl-CoA desaturase-1 and -2, thereby markedly enhancing the production of monounsaturated fatty acids. nSREBP-1c was inactive in stimulating any transcription at the concentrations achieved in these studies. The current data support the emerging view that the nSREBPs act in complementary ways to modulate the lipid composition of cell membranes.",
author = "Pai, {Jih Tung} and Oleg Guryev and Brown, {Michael S.} and Goldstein, {Joseph L.}",
year = "1998",
month = "10",
day = "2",
doi = "10.1074/jbc.273.40.26138",
language = "English (US)",
volume = "273",
pages = "26138--26148",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "40",

}

TY - JOUR

T1 - Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element-binding proteins

AU - Pai, Jih Tung

AU - Guryev, Oleg

AU - Brown, Michael S.

AU - Goldstein, Joseph L.

PY - 1998/10/2

Y1 - 1998/10/2

N2 - Three sterol regulatory element-binding proteins (SREBP-1a, -1c, and - 2) stimulate transcription of genes involved in synthesis and receptor- mediated uptake of cholesterol and fatty acids. Here, we explore the individual roles of each SREBP by preparing lines of Chinese hamster ovary (CHO) cells that express graded amounts of nuclear forms of each SREBP (designated nSREBPs) under control of a muristerone-inducible nuclear receptor system. The parental hamster cell line (M19 cells) lacks its own nSREBPs, owing to a deletion in the gene encoding the Site-2 protease, which releases nSREBPs from cell membranes. By varying the concentration of muristerone, we obtained graded expression of individual nSREBPs in the range that restored lipid synthesis to near physiologic levels. The results show that nSREBP-2 produces a higher ratio of synthesis of cholesterol over fatty acids than does nSREBP-1a. This is due in part to a selective ability of low levels of nSREBP-2, but not nSREBP-1a, to activate the promoter for squalene synthase. nSREBP-1a and -2 both activate transcription of the genes encoding stearoyl-CoA desaturase-1 and -2, thereby markedly enhancing the production of monounsaturated fatty acids. nSREBP-1c was inactive in stimulating any transcription at the concentrations achieved in these studies. The current data support the emerging view that the nSREBPs act in complementary ways to modulate the lipid composition of cell membranes.

AB - Three sterol regulatory element-binding proteins (SREBP-1a, -1c, and - 2) stimulate transcription of genes involved in synthesis and receptor- mediated uptake of cholesterol and fatty acids. Here, we explore the individual roles of each SREBP by preparing lines of Chinese hamster ovary (CHO) cells that express graded amounts of nuclear forms of each SREBP (designated nSREBPs) under control of a muristerone-inducible nuclear receptor system. The parental hamster cell line (M19 cells) lacks its own nSREBPs, owing to a deletion in the gene encoding the Site-2 protease, which releases nSREBPs from cell membranes. By varying the concentration of muristerone, we obtained graded expression of individual nSREBPs in the range that restored lipid synthesis to near physiologic levels. The results show that nSREBP-2 produces a higher ratio of synthesis of cholesterol over fatty acids than does nSREBP-1a. This is due in part to a selective ability of low levels of nSREBP-2, but not nSREBP-1a, to activate the promoter for squalene synthase. nSREBP-1a and -2 both activate transcription of the genes encoding stearoyl-CoA desaturase-1 and -2, thereby markedly enhancing the production of monounsaturated fatty acids. nSREBP-1c was inactive in stimulating any transcription at the concentrations achieved in these studies. The current data support the emerging view that the nSREBPs act in complementary ways to modulate the lipid composition of cell membranes.

UR - http://www.scopus.com/inward/record.url?scp=0032475889&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032475889&partnerID=8YFLogxK

U2 - 10.1074/jbc.273.40.26138

DO - 10.1074/jbc.273.40.26138

M3 - Article

C2 - 9748295

AN - SCOPUS:0032475889

VL - 273

SP - 26138

EP - 26148

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 40

ER -