Schoenheimer effect explained - Feedback regulation of cholesterol synthesis in mice mediated by Insig proteins

Luke Engelking, Guosheng Liang, Robert E Hammer, Kiyosumi Takaishi, Hiroshi Kuriyama, Bret M. Evers, Wei Ping Li, Jay D Horton, Joseph L Goldstein, Michael S Brown

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

End-product feedback inhibition of cholesterol synthesis was first demonstrated in living animals by Schoenheimer 72 years ago. Current studies define Insig proteins as essential elements of this feedback system in mouse liver. In cultured cells, Insig proteins are required for sterol-mediated inhibition of the processing of sterol regulatory element-binding proteins (SREBPs) to their nuclear forms. We produced mice with germline disruption of the Insig2 gene and Cre-mediated disruption of the Insig1 gene in liver. On a chow diet, these double-knockout mice overaccumulated cholesterol and triglycerides in liver. Despite this accumulation, levels of nuclear SREBPs and mRNAs for SREBP target genes in lipogenic pathways were not reduced. Whereas cholesterol feeding reduced nuclear SREBPs and lipogenic mRNAs in wild-type mice, this feedback response was severely blunted in the double-knockout mice, and synthesis of cholesterol and fatty acids was not repressed. The amount of HMG-CoA reductase protein was elevated out of proportion to the mRNA in the double-knockout mice, apparently owing to the failure of cholesterol to accelerate degradation of the enzyme. These studies indicate that the essential elements of the regulatory pathway for lipid synthesis function in liver as they do in cultured cells.

Original languageEnglish (US)
Pages (from-to)2489-2498
Number of pages10
JournalJournal of Clinical Investigation
Volume115
Issue number9
DOIs
StatePublished - Sep 2005

Fingerprint

Sterol Regulatory Element Binding Proteins
Cholesterol
Knockout Mice
Liver
Proteins
Messenger RNA
Cultured Cells
Genes
Hydroxymethylglutaryl CoA Reductases
Sterols
Triglycerides
Fatty Acids
Diet
Lipids
Enzymes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Schoenheimer effect explained - Feedback regulation of cholesterol synthesis in mice mediated by Insig proteins. / Engelking, Luke; Liang, Guosheng; Hammer, Robert E; Takaishi, Kiyosumi; Kuriyama, Hiroshi; Evers, Bret M.; Li, Wei Ping; Horton, Jay D; Goldstein, Joseph L; Brown, Michael S.

In: Journal of Clinical Investigation, Vol. 115, No. 9, 09.2005, p. 2489-2498.

Research output: Contribution to journalArticle

@article{ba4d85eaa1da4ce1b2d38f09eb06f412,
title = "Schoenheimer effect explained - Feedback regulation of cholesterol synthesis in mice mediated by Insig proteins",
abstract = "End-product feedback inhibition of cholesterol synthesis was first demonstrated in living animals by Schoenheimer 72 years ago. Current studies define Insig proteins as essential elements of this feedback system in mouse liver. In cultured cells, Insig proteins are required for sterol-mediated inhibition of the processing of sterol regulatory element-binding proteins (SREBPs) to their nuclear forms. We produced mice with germline disruption of the Insig2 gene and Cre-mediated disruption of the Insig1 gene in liver. On a chow diet, these double-knockout mice overaccumulated cholesterol and triglycerides in liver. Despite this accumulation, levels of nuclear SREBPs and mRNAs for SREBP target genes in lipogenic pathways were not reduced. Whereas cholesterol feeding reduced nuclear SREBPs and lipogenic mRNAs in wild-type mice, this feedback response was severely blunted in the double-knockout mice, and synthesis of cholesterol and fatty acids was not repressed. The amount of HMG-CoA reductase protein was elevated out of proportion to the mRNA in the double-knockout mice, apparently owing to the failure of cholesterol to accelerate degradation of the enzyme. These studies indicate that the essential elements of the regulatory pathway for lipid synthesis function in liver as they do in cultured cells.",
author = "Luke Engelking and Guosheng Liang and Hammer, {Robert E} and Kiyosumi Takaishi and Hiroshi Kuriyama and Evers, {Bret M.} and Li, {Wei Ping} and Horton, {Jay D} and Goldstein, {Joseph L} and Brown, {Michael S}",
year = "2005",
month = "9",
doi = "10.1172/JCI25614",
language = "English (US)",
volume = "115",
pages = "2489--2498",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "9",

}

TY - JOUR

T1 - Schoenheimer effect explained - Feedback regulation of cholesterol synthesis in mice mediated by Insig proteins

AU - Engelking, Luke

AU - Liang, Guosheng

AU - Hammer, Robert E

AU - Takaishi, Kiyosumi

AU - Kuriyama, Hiroshi

AU - Evers, Bret M.

AU - Li, Wei Ping

AU - Horton, Jay D

AU - Goldstein, Joseph L

AU - Brown, Michael S

PY - 2005/9

Y1 - 2005/9

N2 - End-product feedback inhibition of cholesterol synthesis was first demonstrated in living animals by Schoenheimer 72 years ago. Current studies define Insig proteins as essential elements of this feedback system in mouse liver. In cultured cells, Insig proteins are required for sterol-mediated inhibition of the processing of sterol regulatory element-binding proteins (SREBPs) to their nuclear forms. We produced mice with germline disruption of the Insig2 gene and Cre-mediated disruption of the Insig1 gene in liver. On a chow diet, these double-knockout mice overaccumulated cholesterol and triglycerides in liver. Despite this accumulation, levels of nuclear SREBPs and mRNAs for SREBP target genes in lipogenic pathways were not reduced. Whereas cholesterol feeding reduced nuclear SREBPs and lipogenic mRNAs in wild-type mice, this feedback response was severely blunted in the double-knockout mice, and synthesis of cholesterol and fatty acids was not repressed. The amount of HMG-CoA reductase protein was elevated out of proportion to the mRNA in the double-knockout mice, apparently owing to the failure of cholesterol to accelerate degradation of the enzyme. These studies indicate that the essential elements of the regulatory pathway for lipid synthesis function in liver as they do in cultured cells.

AB - End-product feedback inhibition of cholesterol synthesis was first demonstrated in living animals by Schoenheimer 72 years ago. Current studies define Insig proteins as essential elements of this feedback system in mouse liver. In cultured cells, Insig proteins are required for sterol-mediated inhibition of the processing of sterol regulatory element-binding proteins (SREBPs) to their nuclear forms. We produced mice with germline disruption of the Insig2 gene and Cre-mediated disruption of the Insig1 gene in liver. On a chow diet, these double-knockout mice overaccumulated cholesterol and triglycerides in liver. Despite this accumulation, levels of nuclear SREBPs and mRNAs for SREBP target genes in lipogenic pathways were not reduced. Whereas cholesterol feeding reduced nuclear SREBPs and lipogenic mRNAs in wild-type mice, this feedback response was severely blunted in the double-knockout mice, and synthesis of cholesterol and fatty acids was not repressed. The amount of HMG-CoA reductase protein was elevated out of proportion to the mRNA in the double-knockout mice, apparently owing to the failure of cholesterol to accelerate degradation of the enzyme. These studies indicate that the essential elements of the regulatory pathway for lipid synthesis function in liver as they do in cultured cells.

UR - http://www.scopus.com/inward/record.url?scp=24644463295&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24644463295&partnerID=8YFLogxK

U2 - 10.1172/JCI25614

DO - 10.1172/JCI25614

M3 - Article

C2 - 16100574

AN - SCOPUS:24644463295

VL - 115

SP - 2489

EP - 2498

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 9

ER -