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AOP: 548

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased PCSK9 protein expression

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Activation, Pregnane-X receptor leads to increased plasma LDL cholesterol via PCSK9
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.7

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Of the originating work: Anna Itkonen, University of Eastern Finland; Jukka Hakkola, University of Oulu and Oulu University Hospital; Jaana Rysa, University of Eastern Finland.

Of the content populated in the AOP-Wiki:  John R. Frisch and Travis Karschnik, General Dynamics Information Technology; Daniel L. Villeneuve, US Environmental Protection Agency, Great Lakes Toxicology and Ecology Division.  

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
John Frisch   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • John Frisch

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on February 10, 2025 15:34

Revision dates for related pages

Page Revision Date/Time
Activation, Pregnane-X receptor, NR1l2 February 10, 2025 15:38
Decreased, insulin-induced gene 1 (INSIG1) protein activity February 10, 2025 15:52
Increased, Sterol Regulatory Element Binding Protein 2 (SREBP2) protein expression February 10, 2025 15:53
Increased, protein expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) February 10, 2025 16:04
Increased, plasma low-density lipoprotein (LDL) cholesterol February 10, 2025 15:55
Activation, Pregnane-X receptor, NR1l2 leads to Decreased, INSIG1 protein activity February 10, 2025 15:57
Decreased, INSIG1 protein activity leads to Increased, SREBP2 protein expression February 10, 2025 15:58
Increased, SREBP2 protein expression leads to Increased, PCSK9 protein expression February 10, 2025 16:11
Increased, PCSK9 protein expression leads to Increased, plasma LDL cholesterol February 10, 2025 16:12

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Pregnane X receptor (PXR) is a nuclear receptor that, once activated, binds to Retinoid X receptor (RXR), resulting in regulation of target genes, with an important role in maintenance of lipid homeostasis by affecting rates of glucose synthesis, cholesterol synthesis, lipid synthesis, and lipid uptake (Lv et al. 2022).  Increased Pregnane X Receptor (PXR) activation results in decreased insulin-induced gene 1 (INSIG1) protein activity, suggested through destabilization of the INSIG1 protein (Karpale et al. 2021; Itkonen et al. 2023), resulting in decreased lipid uptake. 

Insulin-induced gene 1 (INSIG1) is a transmembrane protein in the endoplasmic reticulum membrane (Ouyang et al. 2020).  INSIG1 has an important role in lipid uptake regulation.  At low cholesterol levels, INSIG1 has lower binding affinity for SREBP cleavage-activating protein (SCAP), allowing free SCAP to bind to Coat Protein Complex II (COPII; Ouyang et al. 2020).  The SCAP-COPII complex enables Sterol Regulatory Element Binding Proteins (SREBPs) to move through the endoplasmic reticulum to the Golgi, where membrane-bound transcription factor site-1-protease (S1P) and site-2-protease (S2P) enable proteolytic processing that allows SREBPs to enter the nucleus (Yabe et al. 2002; Yang et al. 2002).  In the nucleus, SREBP regulate transcription rates, increasing protein expression of proprotein convertase subtilisin/kexin type 9 (PCSK9; Lambert et al. 2006; Seidah et al. 2014).  Proprotein convertase subtilisin/kexin type 9 is also referred to as Neural Apoptosis-Regulated Convertase-1 (NARC-1; Horton et al. 2003; Benjannet et al. 2004). PCSK9 binds to low density lipoprotein receptor (LDLR) on the surface of liver cells, resulting in the degradation of LDLR and decreased uptake of cholesterol (Poirier et al. 2008; Seidah et al. 2014).  At high cholesterol levels, INSIG1 binds to SCAP, competitively inhibiting the ability of SCAP to bind to COPII (Ouyang et al. 2020).  SREBPs are retained in the endoplasmic reticulum rather than being transferred to the Golgi, maintaining levels of cholesterol uptake.

Cholesterol has a variety of roles in organisms, including as a cellular membrane component that helps maintain structure and fluidity, and a precursor for steroid hormones (Sakakura et al. 2001; Horton et al. 2003; Howe et al. 2017).  Decreased uptake of cholesterol results in high levels of plasma low-density lipoprotein (LDL) cholesterol.  Individuals with high levels of plasma low-density lipoprotein (LDL) cholesterol have departed from lipid homeostasis in maintaining cholesterol levels needed for typical function, and in displaying hypercholesterolemia are at greater risk of cardiovascular events (Lalanne et al. 2005; Lambert et al. 2006).  

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

This Adverse Outcome Pathway (AOP) was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  The originating work for this AOP was: Itkonen, A., Hakkola, J., and Rysa, J.  2023.  Adverse outcome pathway for pregnane X receptor‑induced Hypercholesterolemia.  Archives of Toxicology 97: 2861–2877.   This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages. 

The focus of the originating work was to use an AOP framework to investigate the mechanisms linking Pregnane X receptor (PXR) activation to increased plasma low-density lipoprotein (LDL) cholesterol.  Itkonen et al. (2023) provided network analysis from a literature search to assess the empirical evidence, biological plausibility and domain of applicability for each developed key event and key event relationship.   Available evidence provided support of mechanisms for increased plasma low-density lipoprotein (LDL) cholesterol through multiple pathways, including: 1. Increased, cholesterol synthesis enzymes; 2. Increased, protein expression of proprotein convertase subtilisin/kexin type 9 (PCSK9).  In this AOP, we focus on the pathway through Increased, protein expression of proprotein convertase subtilisin/kexin type 9 (PCSK9).   Empirical studies were primarily from laboratory rodents and humans.  

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

The originating authors conducted a literature search to develop a database of publications categorized by discipline or field of study: toxicology, epidemiology, exposure, and gene-environment interaction. The literature search relied on standard search engines such as Web of Science and Google Scholar, and the search strategy focused on mechanisms linking PXR activation to increased level of plasma LDL cholesterol in organisms. The originating authors reviewed references from individual citations to identify additional studies not captured through the literature search itself.   They then included all relevant publications through 2023. 

The scope of the aforementioned EPA project was limited to re-representing the AOP(s) as presented in the originating publication. The literature used to support this AOP and its constituent pages began with the originating publication and followed to the primary, secondary, and tertiary works cited therein. KE and KER page creation and re-use was determined using Handbook principles where page re-use was preferred.    

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 239 Activation, Pregnane-X receptor, NR1l2 Activation, Pregnane-X receptor, NR1l2
AO 2271 Increased, plasma low-density lipoprotein (LDL) cholesterol Increased, plasma LDL cholesterol

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages Moderate

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
mammals mammals High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

1. Support for Biological Plausibility of Key Event Relationships: Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge?

Key Event Relationship (KER)

Level of Support  

Strong = Extensive understanding of the KER based on extensive previous documentation and broad acceptance.

Moderate = Support of the relationship based on empirical studies, with some uncertainty of the direction of the response (decreased or increased) and the mechanism.

Relationship 3365: Activation Pregnane-X receptor, NR1l2 leads to Decreased, INSIG1 protein activity

Moderate support.  The relationship between activation of pregnane-X receptor and INSIG1 protein activity is broadly accepted in humans and laboratory mammals, but there are some empirical studies where activation of Pregnane-X receptor leads to increased INSIG protein activity, the opposite direction from the mechanism of the AOP.  Destabilization of the INSIG1 protein has been the suggested mechanism (Karpale et al. 2021; Itkonen et al. 2023).

Relationship 3366: Decreased, INSIG1 protein activity leads to Increased, SREBP2 protein expression

Strong support.  The relationship between decreased INSIG protein activity and increased SREBP2 protein expression is broadly accepted and supported among humans and laboratory mammal data.

Relationship 3388: Increased, SREBP2 protein expression leads to Increased, PCSK9 protein expression

Strong support. The relationship between increased SREBP2 protein expression and increased PCSK9 protein expression is broadly accepted and supported among humans and laboratory mammal data.

Relationship 3389: Increased, PCSK9 protein expression leads to Increased, plasma LDL cholesterol

Strong support.  The relationship between increased PCSK9 protein expression and increased plasma LDL cholesterol is broadly accepted and supported among humans and laboratory mammal data.

Overall

Moderate to strong support.  Extensive understanding of the relationships between events from empirical studies from humans and laboratory mammals, with some inconsistency of the direction of the response in INSIG1 protein activity from Pregnane-X receptor activation.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Life Stage: All life stages.

Sex: Applies to both males and females.

Taxonomic: Primarily studied in humans and laboratory rodents.  

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

2. Essentiality of Key Events: Are downstream KEs and/or the AO prevented if an upstream KE is blocked?

Key Event (KE)

Level of Support

Strong = Direct evidence from specifically designed experimental studies illustrating essentiality and direct relationship between key events.

Moderate = Indirect evidence from experimental studies inferring essentiality of relationship between key events due to difficulty in directly measuring at least one of key events, or some question of the direction of the response (decreased or increased).

KE 239 Activation Pregnane-X receptor, NR1l2

Moderate support.  Activation of Pregnane-X receptor is linked to INSIG1 protein uptake, but there are some empirical studies where activation of Pregnane-X receptor leads to increased INSIG protein activity, the opposite direction from the mechanism of the AOP.  Evidence is available from toxicant, diet, and gene-knockout studies measuring gene expression and protein levels.  Best evidence for essentiality of activation of Pregnane-X receptor is in toxicant and diet studies leading to decreased INSIG1 activity, with normal INSIG1 activity in the absence of stressor.  Additional studies examining the conditions required for INSIG1 protein stability, and the relationship between INSIG1 gene and protein levels in the presence/absence of stressors, would be beneficial.

KE 2268 Decreased, INSIG1 protein activity

Strong support.  Decreased INSIG 1 protein activity is linked to increased SREBP2 protein expression.  Evidence is available from gene-knockout, gene transfection, and diet studies measuring gene expression and protein levels.  Best evidence for essentiality of INSIG1 protein is in gene and diet studies showing INSIG1 protein levels and SREBP2 protein levels in the endoplasmic reticulum and nucleus, as inactive SREBP2 is known to be bound to the endoplasmic reticulum, and needs to be transferred to the Golgi by escort proteins for activation to regulate downstream loci.  High levels of INSIG1 protein have been established to bind to SREBP cleavage-activating protein (SCAP) and promote retention of inactive SREBP2 in the endoplasmic reticulum; low levels of INSIG1 protein allow SCAP to bind to SREBP2 and increase transfer rates to the Golgi.

KE 2269 Increased, SREBP2 protein expression

Strong support.  Increased SREBP2 protein activity is linked to increased PCSK9 protein expression.  Evidence is available from gene-knockout, gene transfection, and diet studies measuring gene expression and protein levels.  Best evidence for essentiality of SREBP2 protein is in studies showing that SREBP2 proteins binds to the promoter site of PCSK9 protein expression to activate transcription, in gene knock-out studies where decreased SREBP2 protein expression led to decreased PCSK9 protein expression, and in gene overexpression studies where decreased SREBP2 protein expression led to decreased PCSK9 protein expression.

KE 2276 Increased, PCSK9 protein expression

Strong support. Increased PCSK9 protein expression is linked to increased plasma LDL cholesterol.  Evidence is available from gene-knockout, gene transfection, and diet studies measuring protein levels.  Best evidence for essentiality of PCSK9 protein expression are studies showing that increases in PCSK9 protein expression lead to increased plasma LDL cholesterol.  However, increased plasma LDL cholesterol can be caused by additional mechanisms, including increased intake of cholesterol in diet, increased cholesterol synthesis, and decreased efflux and excretion.

KE 2271 Increased, plasma LDL cholesterol

This is the final event of the AOP.

Overall

Moderate to strong support.  Direct evidence from empirical studies from laboratory mammals and human cell lines for most key events, with more inferential evidence for events occurring in cells and tissues.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

3. Empirical Support for Key Event Relationship: Does empirical evidence support that a  change in KEup leads to an appropriate change in KEdown?

Key Event Relationship (KER)

Level of Support 

Strong =  Experimental evidence from exposure to toxicant shows consistent change in both events across taxa and study conditions. 

Moderate = Support of the relationship based on empirical studies, with some uncertainty of the direction of the response (decreased or increased).

Relationship 3365: Activation Pregnane-X receptor, NR1l2 leads to Decreased, INSIG1 protein activity

Moderate support.  Activation of Pregnane-X receptor leads to decreased INSIG1 protein activity from toxicant, diet, and gene-knockout studies.  Some studies show activation of Pregnane-X receptor leads to an increase in INSIG1 protein activity, the opposite direction from the mechanism of the AOP.  Activation of Pregnane-X receptor occurred earlier in the time-course of exposure than decreased INSIG1 protein activity, and the concentrations that activated Pregnane-X receptor were equal to or lower than the concentrations that decreased INSIG1 protein activity.  Therefore, the data support a causal relationship.

Relationship 3366: Decreased, INSIG1 protein activity leads to Increased, SREBP2 protein expression

Strong support. Decreased INSIG1 protein activity leads to increased SREBP2 protein expression from gene-knockout, gene transfection, and diet studies.  Decreased INSIG1 protein activity occurred earlier in the time-course of exposure than increased SREBP2 protein expression, and the concentrations that decreased INSIG1 protein activity were equal to or lower than the concentrations that increased SREBP2 protein expression.  Therefore, the data support a causal relationship.

Relationship 3388: Increased, SREBP2 protein expression leads to Increased, PCSK9 protein expression

Strong support. Increased SREBP2 protein expression leads to increased PCSK9 protein expression from gene-knockout, gene transfection, and diet studies.  Increased SREBP2 protein expression occurred earlier in the time-course of exposure than increased PCSK9 protein expression, and the concentrations that increased SREBP2 protein expression were equal to or lower than the concentrations that increased PCSK9 protein expression.  Therefore, the data support a causal relationship.

Relationship 3389: Increased, PCSK9 protein expression leads to Increased, plasma LDL cholesterol

Strong support. Increased PCSK9 protein expression leads to increased plasma LDL cholesterol from gene-knockout, gene transfection, and diet studies.  Increased PCSK9 protein expression occurred earlier in the time-course of exposure than increased plasma LDL cholesterol, and the concentrations that increased PCSK9 protein expression were equal to or lower than the concentrations that increased plasma LDL cholesterol.  Therefore, the data support a causal relationship.

Overall

Moderate to strong support.  Evidence from empirical studies shows consistent change in both events including frequent testing in lab mammals, with upstream events occurring earlier in the time-course of exposure and at equal or lower concentrations than downstream events, supporting causal relationships.  The relationship between Pregnane-X receptor and INSIG 1 protein activity is a possible exception, as there are some studies that show activation of Pregnane-X receptor leads to an increase in INSIG1 protein activity, the opposite direction from the mechanism of the AOP.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

Benjannet, S., Rhainds, D., Essalmani, R., Mayne, J., Wickham, L., Jin, W., Asselin, M.-C., Hemelin, J., Varret, M., Allrd, D., Trillard, M., Abifadel, M., Tebon, T., Attie, A.D., Rader, D.J., Boileau, C., Brissette, L., Chretien, M., Prat, A., and Seidah, N.G.  2004. NARC-1/PCSK9 and its natural mutants: Zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.   The Journal of Biological Chemistry.  279(47): 48865–48875.

Horton, J.D., Shah, N.A., Warrington, J.A., Anderson, N.N., Park, S.W., Brown, M.S., and Goldstein, J.L.  2003. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes.  Proceedings of the National Academy of Sciences 100(21): 12027–12032.

Howe, V., Sharpe, L.J., Prabhu, A.V., and Brown, A.J.  2017.  New insights into cellular cholesterol acquisition: promoter analysis of human HMGCR and SQLE, two key control enzymes in cholesterol synthesis.  Biochim Biophys Acta 1862: 647–657.

Itkonen, A., Hakkola, J., and Rysa, J.  2023.  Adverse outcome pathway for pregnane X receptor‑induced Hypercholesterolemia.  Archives of Toxicology 97: 2861–2877.

Karpale, M.  Karajamaki, A.J., Kummu, O., Gylling, H., Hyotylainen, T., Oresic, M., Tolonen, A., Hautajarvi, H., Savolainen, M.J., Ala-Korpela, M., Hukkanen, J., and Hakkola, J.  2021.  Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism.  British Journal of Pharmacology  178: 2461–2481.

Lalanne, F., Lambert, G., Amar, M.J.A., Chetiveaux, M., Zair, Y., Jarnoux, A.-L., Ouguerram, K., Friburg, J., Seidah, N.G., Brewer, Jr., H.B., Krempf, M., and Costet, P.  2005.  Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells.  Journal of Lipid Research 46: 1312–1319.

Lambert, G., Jarnoux, A.-J., Pineau, T., Pape, O., Chetiveaux, M., Laboisse, C., Krempf, M., and Costet, P.  2006.  Fasting induces hyperlipidemia in mice overexpressing Proprotein Convertase Subtilisin Kexin Type 9: Lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor.  Endocrinology 147(10): 4985–4995.

Lv, Y., Luo, Y.-Y., Ren, H.-W., Li, C.-J., Xiang, Z.-X., and Luan, Z.L.  2022.  The role of pregnane X receptor (PXR) in substance metabolism.  Frontiers in Endocrinology 13: 959902.

Ouyang, S., Mo, Z., Sun, S., Yin, K., and Lv, Y.  2020.  Emerging role of Insig-1 in lipid metabolism and lipid disorders.  Clinica Chimica Acta 508: 206–212.

Poirier, S., Mayer, G., Benjannet, S., Bergeron, E., Marcinkiewicz, J., Nassoury, N., Mayer, H., Nimpf, J., Prat, A., and Seidah, N.G.  2008.  The Proprotein Convertase PCSK9 induces the degradation of Low Density Lipoprotein Receptor (LDLR) and Its closest family members VLDLR and ApoER2.  The Journal of Biological Chemistry 283(4): 2363-2372.

Sakakura, Y., Shimano, H., Sone, H., Takahashi, A., Inoue, N., Toyshima, H., Suzuki, S. and Yamada, N.  2001.  Sterol regulatory element-binding proteins induce an entire pathway of cholesterol synthesis. Biochemical and Biophysical Research Communications 286: 176–183.

Seidah, N.G., Awan, Z., Chretien, M., and Mbikay, M.  2014.  PCSK9: A key modulator of cardiovascular health.  Circulation Research 114(6): 1022-1036.

Yabe, D., Brown, M.S., and Goldstein, J.L.  2002.  Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins.  Proceedings of the National Academy of Sciences 99(20): 12753–12758.

Yang, T., Espenshade, P.J., Wright, M.E., Yabe, D., Gong, Y., Aebersold, R., Goldstein, J.L., and Brown, M.S.  2002.  Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110: 489–500.