Effectors of Rapid Homeostatic Responses of Endoplasmic Reticulum Cholesterol and 3-Hydroxy-3-methylglutaryl-CoA Reductase

The cholesterol content of the endoplasmic reticulum (ER) and the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) imbedded therein respond homeostatically within minutes to changes in the level of plasma membrane cholesterol. We have now examined the roles of sterol regulatory element-binding protein (SREBP)-dependent gene expression, side chain oxysterol biosynthesis, and cholesterol precursors in the short term regulation of ER cholesterol levels and HMGR activity. We found that SREBP-dependent gene expression is not required for the response to changes in cell cholesterol of either the pool of ER cholesterol or the rate of cholesterol esterification. It was also found that the acute proteolytic inactivation of HMGR triggered by cholesterol loading required the conversion of cholesterol to 27-hydroxycholesterol. High levels of exogenous 24,25-dihydrolanosterol drove the inactivation of HMGR; lanosterol did not. However, purging endogenous 24,25-dihydrolanosterol, lanosterol, and other biosynthetic sterol intermediates by treating cells with NB-598 did not greatly affect either the setting of their ER cholesterol pool or the inactivation of their HMGR. In summary, neither SREBP-regulated genes nor 27-hydroxycholesterol is involved in setting the ER cholesterol pool. On the other hand, 27-hydroxycholesterol, rather than cholesterol itself or biosynthetic precursors of cholesterol, stimulates the rapid inactivation of HMGR in response to high levels of cholesterol.

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A role for smooth endoplasmic reticulum membrane cholesterol ester in determining the intracellular location and regulation of sterol-regulatory-element-binding protein-2

Biochemical Journal ◽

10.1042/bj3580415 ◽

2001 ◽

Vol 358 (2) ◽

pp. 415-422 ◽

Cited By ~ 7

Author(s):

Christopher R. IDDON ◽

Jane WILKINSON ◽

Andrew J. BENNETT ◽

Julie BENNETT ◽

Andrew M. SALTER ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cholesterol Ester ◽

Smooth Endoplasmic Reticulum ◽

Regulatory Element ◽

Membrane Cholesterol ◽

Endoplasmic Reticulum Membrane ◽

Cellular Cholesterol ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Coa Reductase

Cellular cholesterol homoeostasis is regulated through proteolysis of the membrane-bound precursor sterol-regulatory-element-binding protein (SREBP) that releases the mature transcription factor form, which regulates gene expression. Our aim was to identify the nature and intracellular site of the putative sterol-regulatory pool which regulates SREBP proteolysis in hamster liver. Cholesterol metabolism was modulated by feeding hamsters control chow, or a cholesterol-enriched diet, or by treatment with simvastatin or with the oral acyl-CoA:cholesterol acyltransferase inhibitor C1-1011 plus cholesterol. The effects of the different treatments on SREBP activation were confirmed by determination of the mRNAs for the low-density lipoprotein receptor and hydroxymethylglutaryl-CoA (HMG-CoA) reductase and by measurement of HMG-CoA reductase activity. The endoplasmic reticulum was isolated from livers and separated into subfractions by centrifugation in self-generating iodixanol gradients. Immunodetectable SREBP-2 accumulated in the smooth endoplasmic reticulum of cholesterol-fed animals. Cholesterol ester levels of the smooth endoplasmic reticulum membrane (but not the cholesterol levels) increased after cholesterol feeding and fell after treatment with simvastatin or C1-1011. The results suggest that an increased cellular cholesterol load causes accumulation of SREBP-2 in the smooth endoplasmic reticulum and, therefore, that membrane cholesterol ester may be one signal allowing exit of the SREBP-2/SREBP-cleavage-regulating protein complex to the Golgi.

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Quercetin up-regulates paraoxonase 1 gene expression via sterol regulatory element binding protein 2 that translocates from the endoplasmic reticulum to the nucleus where it specifically interacts with sterol responsive element–like sequence in paraoxonase 1 promoter in HuH7 liver cells

Metabolism ◽

10.1016/j.metabol.2009.12.025 ◽

2010 ◽

Vol 59 (9) ◽

pp. 1372-1378 ◽

Cited By ~ 21

Author(s):

Mamatha Garige ◽

Maokai Gong ◽

Ravi Varatharajalu ◽

M. Raj Lakshman

Keyword(s):

Gene Expression ◽

Endoplasmic Reticulum ◽

Binding Protein ◽

Regulatory Element ◽

Liver Cells ◽

Paraoxonase 1 ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Responsive Element

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Faculty Opinions recommendation of Sterol regulatory element-binding protein-2- and liver X receptor-driven dual promoter regulation of hepatic ABC transporter A1 gene expression: mechanism underlying the unique response to cellular cholesterol status.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1090217.543438 ◽

2007 ◽

Author(s):

Axel Nohturfft

Keyword(s):

Gene Expression ◽

Abc Transporter ◽

Regulatory Element ◽

Liver X Receptor ◽

Promoter Regulation ◽

Cellular Cholesterol ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Cholesterol Status ◽

Expression Mechanism

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Sterol regulatory element binding protein-1 (SREBP1) gene expression is similarly increased in polycystic ovary syndrome and endometrial cancer

Acta Obstetricia Et Gynecologica Scandinavica ◽

10.1111/aogs.13106 ◽

2017 ◽

Vol 96 (5) ◽

pp. 556-562 ◽

Cited By ~ 7

Author(s):

Mohamad N. Shafiee ◽

Nigel Mongan ◽

Claire Seedhouse ◽

Caroline Chapman ◽

Suha Deen ◽

...

Keyword(s):

Gene Expression ◽

Endometrial Cancer ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Binding Protein ◽

Regulatory Element ◽

Ovary Syndrome ◽

Element Binding Protein ◽

Sterol Regulatory Element

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Linalool reduces the expression of 3-hydroxy-3-methylglutaryl CoA reductase via sterol regulatory element binding protein-2- and ubiquitin-dependent mechanisms

FEBS Letters ◽

10.1016/j.febslet.2011.09.012 ◽

2011 ◽

Vol 585 (20) ◽

pp. 3289-3296 ◽

Cited By ~ 28

Author(s):

Sung-Yun Cho ◽

Hee-jin Jun ◽

Ji Hae Lee ◽

Yaoyao Jia ◽

Kyoung Heon Kim ◽

...

Keyword(s):

Binding Protein ◽

Regulatory Element ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Coa Reductase

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Sterol Regulatory Element-binding Protein-2- and Liver X Receptor-driven Dual Promoter Regulation of Hepatic ABC Transporter A1 Gene Expression

Journal of Biological Chemistry ◽

10.1074/jbc.m701228200 ◽

2007 ◽

Vol 282 (29) ◽

pp. 21090-21099 ◽

Cited By ~ 76

Author(s):

Norimasa Tamehiro ◽

Yukari Shigemoto-Mogami ◽

Tomoshi Kakeya ◽

Kei-ichiro Okuhira ◽

Kazuhiro Suzuki ◽

...

Keyword(s):

Gene Expression ◽

Abc Transporter ◽

Binding Protein ◽

Regulatory Element ◽

Liver X Receptor ◽

Promoter Regulation ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Dual Promoter

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Sex-specific effects of in vitro fertilization on adult metabolic phenotypes and hepatic transcriptomic and proteomic pathways in mouse

10.1101/2020.09.23.309989 ◽

2020 ◽

Author(s):

Laren Narapareddy ◽

Eric A. Rhon-Calderon ◽

Lisa A. Vrooman ◽

Josue Baeza ◽

Duy K. Nguyen ◽

...

Keyword(s):

Regulatory Element ◽

Perinatal Outcomes ◽

Vitro Fertilization ◽

Specific Effects ◽

Cholesterol Levels ◽

Element Binding Protein ◽

Fat Composition ◽

Sterol Regulatory Element

AbstractAlthough in vitro fertilization (IVF) is associated with adverse perinatal outcomes, an increasing concern is the long-term health implications. We augmented our IVF mouse model to longitudinally investigate cardiometabolic outcomes in offspring from optimal neonatal litter sizes. We found that IVF-conceived females had higher body weight and cholesterol levels compared to naturally-conceived females, whereas IVF-conceived males had higher levels of triglycerides and insulin, and increased body fat composition. Through transcriptomics and proteomics of adult liver, we identified sexually-dimorphic dysregulation of the sterol regulatory element binding protein (SREBP) pathways that are associated with the sex-specfic phenotypes. We also found that global loss of DNA methylation in placenta was linked to higher cholesterol levels in IVF-conceived females. Our findings indicate that IVF procedures have long-lasting sex-specific effects on metabolic health of offspring and lay the foundation to utilize the placenta as a predictor of long-term outcomes.

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