Cholesterol in LDL receptor recycling and degradation

Hui-xian, Yang; Zhang, Min; Long, Shiyin; Tuo, Qin-Hui; Tian, Ying; Chen, Jianxiong; Zhang, Caiping; Liao, Duan‐Fang

doi:10.1016/j.cca.2019.09.022

Cited by 71 publications

(50 citation statements)

References 61 publications

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“…SREBP-2 and SCAP (SREBP cleavage-activating protein) integrate a sensor of cholesterol in the endoplasmic reticulum, subtly regulating intracellular cholesterol concentrations. Moreover, LDL-R concentration in plasmatic membranes is modulated by three factors: the activity of SREBP-2, the pro-protein convertase subtilisin/ kexin type 9 (PCSK9) expression and, the inducible degrader of LDL-R (IDOL) [67]. Considering the critical role of LDL-R in neoplastic phenomena, specifically the regulation of PCSK9 and IDOL has not been characterized in detail under a tumoral environment.…”

Section: The Role Of Sterol Regulatory Element-binding Protein 2 (Srebp-2)mentioning

confidence: 99%

Impact of cholesterol-pathways on breast cancer development, a metabolic landscape

González-Ortiz¹,

Galindo-Hernández²,

Hernández-Acevedo³

et al. 2021

J. Cancer

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ApoB-lipoproteins and their components modulate intracellular metabolism and have been associated with the development of neoplastic phenomena, such as proliferation, anchorage-independent growth, epithelial-mesenchymal transition, and cancer invasion. In cancer cells, the modulation of targets that regulate cholesterol metabolism, such as synthesis de novo, endocytosis, and oxidation, are contributing factors to cancer development. While mechanisms associated with sterol regulatory element-binding protein 2 (SREBP-2)/mevalonate, the low-density lipoprotein receptor (LDL-R) and liver X receptor (LXR) have been linked with tumor growth; metabolites derived from cholesterol-oxidation, such as oxysterols and epoxy-cholesterols, also have been described as tumor processes-inducers. From this notion, we perform an analysis of the role of lipoproteins, their association with intracellular cholesterol metabolism, and the impact of these conditions on breast cancer development, mechanisms that can be shared during atherogenesis promoted mainly by LDL. Pathways connecting plasma dyslipidemias in conjunction with the effect of cholesterol-derived metabolites on intracellular mechanisms and cellular plasticity phenomena could provide new approaches to elucidate the triggering factors of carcinogenesis, conditions that could be considered in the development of new therapeutic approaches.

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Section: The Role Of Sterol Regulatory Element-binding Protein 2 (Srebp-2)mentioning

confidence: 99%

Impact of cholesterol-pathways on breast cancer development, a metabolic landscape

González-Ortiz¹,

Galindo-Hernández²,

Hernández-Acevedo³

et al. 2021

J. Cancer

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“…Intracellular PCSK9 and LDLR protein levels were significantly increased in HepG2 cells when the cells were cultured in lipid-deficient media, which was significantly suppressed by the treatment of CBE (50 μg/mL). LDLR protein expression was unchanged by CBE, which can likely be attributed to PCSK9 downregulation, thereby preventing LDLR lysosomal degradation [24]. CBE-mediated PCSK9 inhibition was likely associated with decreased SREBP2 and HNF-1α in HepG2 cells.…”

Section: Discussionmentioning

confidence: 93%

“…We have previously found that a Welsh onion ethanol extract and its active compound, kaempferol, acts as a PCSK9 inhibitor via SREBP2 downregulation in HepG2 cells. Since LDLR and PCSK9 both contain sterol regulatory elements within their promoter, SREBP2 can stimulate the transcription of both the LDLR and PCSK9 genes [24]. The transcription factor HNF-1α is another important transactivational mediator of PCSK9 that positively regulates PCSK9 gene expression.…”

Section: Discussionmentioning

confidence: 99%

The Cholesterol-Lowering Effect of Capsella Bursa-Pastoris Is Mediated via SREBP2 and HNF-1α-Regulated PCSK9 Inhibition in Obese Mice and HepG2 Cells

Choi

Park

et al. 2021

Foods

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The objective of the present study was to investigate the mechanism by which capsella bursa-pastoris ethanol extract (CBE), containing 17.5 milligrams of icaritin per kilogram of the extract, and icaritin, mediate hypocholesterolemic activity via the low-density lipoprotein receptor (LDLR) and pro-protein convertase subtilisin/kexin type 9 (PCSK9) in obese mice and HepG2 cells. CBE significantly attenuated serum total and LDL cholesterol levels in obese mice, which was associated with significantly decreased PCSK9 gene expression. HepG2 cells were cultured using delipidated serum (DLPS), and CBE significantly reduced PCSK9 and maintained the LDLR level. CBE co-treatment with rosuvastatin attenuated statin-mediated PCSK9 expression, and further increased LDLR. The icaritin contained in CBE decreased intracellular PCSK9 and LDLR levels by suppressing transcription factors SREBP2 and HNF-1α. Icaritin also significantly suppressed the extracellular PCSK9 level, which likely contributed to post-translational stabilization of LDLR in the HepG2 cells. PCSK9 inhibition by CBE is actively attributed to icaritin, and the use of CBE and icaritin could be an alternative therapeutic approach in the treatment of hypercholesterolemia.

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“…The liver also takes up low density lipoprotein (LDL) via the recognition of apolipoproteins by LDL receptors (LDLR) [108]. LDLR is polyubiquitinated by an E3-ubiqutinase-inducible degrader of LDLR (IDOL) and subjected to proteasome-dependent degradation [109]. Both USP2-1 and USP2-4 deubiquitinate and stabilize IDOL, suggesting that USP2 promotes LDLR degradation [110].…”

Section: Energy Metabolism and Metabolic Disordersmentioning

confidence: 99%

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

Kitamura

Hashimoto

2021

IJMS

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Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells. Usp2 knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models.

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Cholesterol in LDL receptor recycling and degradation

Cited by 71 publications

References 61 publications

Impact of cholesterol-pathways on breast cancer development, a metabolic landscape

Impact of cholesterol-pathways on breast cancer development, a metabolic landscape

The Cholesterol-Lowering Effect of Capsella Bursa-Pastoris Is Mediated via SREBP2 and HNF-1α-Regulated PCSK9 Inhibition in Obese Mice and HepG2 Cells

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

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