PAQR3 modulates cholesterol homeostasis by anchoring Scap/SREBP complex to the Golgi apparatus

Xu, Daqian; Wang, Zheng; Zhang, Yuxue; Jiang, Wei; Pan, Yi; Song, Bao-Liang; Chen, Yan

doi:10.1038/ncomms9100

Cited by 70 publications

(60 citation statements)

References 41 publications

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“…Our group recently found that PAQR3 can regulate autophagy by integrating AMPK signaling upon glucose starvation . Intriguingly, PAQR3 also regulates anabolism by elevating cholesterol homeostasis by anchoring the Scap/SREBP2 complex to the Golgi apparatus . In this study, we demonstrate that PAQR3 is an important regulator of lipid catabolism by regulating PPARα polyubiquitination/degradation, thereby modulating the hepatic functions of PPARα.…”

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confidence: 60%

Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1

Zhao

Wang

et al. 2018

Hepatology

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Peroxisome proliferator‐activated receptor α (PPARα) is a key transcriptional factor that regulates hepatic lipid catabolism by stimulating fatty acid oxidation and ketogenesis in an adaptive response to nutrient starvation. However, how PPARα is regulated by posttranslational modification is poorly understood. In this study, we identified that progestin and adipoQ receptor 3 (PAQR3) promotes PPARα ubiquitination through the E3 ubiquitin ligase HUWE1, thereby negatively modulating PPARα functions both in vitro and in vivo. Adenovirus‐mediated Paqr3 knockdown and liver‐specific deletion of the Paqr3 gene reduced hepatic triglyceride levels while increasing fatty acid oxidation and ketogenesis upon fasting. PAQR3 deficiency enhanced the fasting‐induced expression of PPARα target genes, including those involved in fatty acid oxidation and fibroblast growth factor 21, a key molecule that mediates the metabolism‐modulating effects of PPARα. PAQR3 directly interacted with PPARα and increased the polyubiquitination and proteasome‐mediated degradation of PPARα. Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARα polyubiquitination. Additionally, PAQR3 enhanced the interaction between HUWE1 and PPARα. Conclusion: Ubiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPARα in response to starvation. (Hepatology 2018;68:289‐303).

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confidence: 60%

Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1

Zhao

Wang

et al. 2018

Hepatology

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“…Cholesterol plays important roles in animal and cellular membranous structures and serves as a precursor for steroid hormones and bile acids . In addition, it has been identified as a major factor in the pathogenesis of atherosclerosis, myocardial infarction, and strokes .…”

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confidence: 99%

“…3‐Hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) acts as the key rate‐limiting enzyme in cholesterol synthesis and the primary site of feedback regulation . Several transcription factors, including sterol regulatory element (SRE) binding protein 2 (SREBP‐2), SREBP‐1a, liver X receptor, and forkhead box O (FoxO) transcription factors, have been linked to cholesterol regulation in the liver .…”

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confidence: 99%

A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP‐2

Song

Zhao

et al. 2017

Hepatology

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Cholesterol synthesis is regulated by the transcription factor sterol regulatory element binding protein 2 (SREBP‐2) and its target gene 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR), which is the rate‐limiting enzyme in cholesterol synthesis. Cyclic adenosine monophosphate–responsive element (CRE) binding protein–regulated transcription coactivator (CRTC) 2 is the master regulator of glucose metabolism. However, the effect of CRTC2 on cholesterol and its potential molecular mechanism remain unclear. Here, we demonstrated that CRTC2 expression and liver cholesterol content were increased in patients with high serum cholesterol levels who underwent resection of liver hemangiomas, as well as in mice fed a 4% cholesterol diet. Mice with adenovirus‐mediated CRTC2 overexpression also showed elevated lipid levels in both serum and liver tissues. Intriguingly, hepatic de novo cholesterol synthesis was markedly increased under these conditions. In contrast, CRTC2 ablation in mice fed a 4% cholesterol diet (18 weeks) showed decreased lipid levels in serum and liver tissues compared with those in littermate wild‐type mice. The expression of lipogenic genes (SREBP‐2 and HMGCR) was consistent with hepatic CRTC2 levels. In vivo imaging showed enhanced adenovirus‐mediated HMGCR‐luciferase activity in adenovirus‐mediated CRTC2 mouse livers; however, the activity was attenuated after mutation of CRE or sterol regulatory element sequences in the HMGCR reporter construct. The effect of CRTC2 on HMGCR in mouse livers was alleviated upon SREBP‐2 knockdown. CRTC2 modulated SREBP‐2 transcription by CRE binding protein, which recognizes the half‐site CRE sequence in the SREBP‐2 promoter. CRTC2 reduced the nuclear protein expression of forkhead box O1 and subsequently increased SREBP‐2 transcription by binding insulin response element 1, rather than insulin response element 2, in the SREBP‐2 promoter. Conclusion: CRTC2 regulates the transcription of SREBP‐2 by interfering with the recognition of insulin response element 1 in the SREBP‐2 promoter by forkhead box O1, thus inducing SREBP‐2/HMGCR signaling and subsequently facilitating hepatic cholesterol synthesis. (Hepatology 2017;66:481–497).

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“…Whereas Insig-1 retains Scap/SREBP in the ER, a Golgi-localized membrane protein progestin and adipoQ receptors 3 (PAQR3) was recently identified as interacting with Scap/ SREBP to tether them to the Golgi (26). To determine whether Wnt5a modifies Insig-1 levels, we used SDS-PAGE and immunoblotting to follow the disappearance of total Insig-1 after protein synthesis was blocked by cycloheximide.…”

Section: Wnt5a-re-transfected Lrp1mentioning

confidence: 99%

Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation

Asmar

Terrand

Jenty

et al. 2016

Journal of Biological Chemistry

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The low density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitously expressed cell surface receptor that protects from intracellular cholesterol accumulation. However, the underlying mechanisms are unknown. Here we show that the extracellular (␣) chain of LRP1 mediates TGF␤-induced enhancement of Wnt5a, which limits intracellular cholesterol accumulation by inhibiting cholesterol biosynthesis and by promoting cholesterol export. Moreover, we demonstrate that the cytoplasmic (␤) chain of LRP1 suffices to limit cholesterol accumulation in LRP1؊/؊ cells. Cholesterol is a major component of mammalian cell membranes that accumulates in the vascular wall during atherosclerosis, the leading cause of death in industrialized societies (1, 2). The low density lipoprotein receptor-related protein 1 (LRP1), 3 a cell surface receptor that belongs to the LDL receptor family, endocytoses multiple ligands (3). It consists of an 85-kDa membrane-bound carboxyl fragment (␤ chain) and a non-covalently attached 515-kDa (␣ chain) amino-terminal fragment (4). We previously demonstrated that LRP1 limits cholesterol accumulation in the arterial wall. Mice deficient for LRP1 in vascular smooth muscle cells (vSMCs) (smLRP1 mice) develop vSMCs proliferation, cholesterol accumulation (5), and massive foam cell formation when fed a cholesterol-rich diet (6 -10). Whereas LRP1 integrates the platelet-derived growth factor (PDGF-BB) (8, 9) and transforming growth factor-␤ (TGF-␤) at the plasma membrane, two pathways known to regulate vSMCs proliferation (7), the physiological importance and function of LRP1 in regulating intracellular cholesterol homeostasis is still poorly understood. Several mechanisms have been proposed. LRP1 has been shown to promote cholesterol export in vSMCs through induction of ATP binding cassette transporter A1 (ABCA1) levels (5) and to induce a Wnt5a/␤-catenin pathway to limit cholesterol overload in mouse embryonic fibroblasts (11). Moreover, smLRP1 mice express very low levels of Wnt5a in vSMCs (12). TGF-␤ also stimulates a non-canonical Wnt5a pathway in airway smooth muscle cells (13). These data strongly suggest that a TGF-␤/LRP1/Wnt5a pathway limits intracellular cholesterol accumulation.How Wnt5a interferes with cholesterol homeostasis is unknown. It might increase cholesterol export and/or block cholesterol synthesis. ABCA1 and the ATP binding cassette transporter G1 (ABCG1) are two proteins that promote cholesterol efflux. Cholesterol synthesis is tightly regulated by a feedback system that senses the level of cholesterol and modulates the transcription of genes encoding enzymes of cholesterol biosynthesis and uptake (14, 15). For instance, when cholesterol levels rise in cells, the membrane-embedded protein of the endoplasmic reticulum (ER), Scap, senses the increase and binds to Insigs, proteins located to the ER. Insigs then limit cleavage and nuclear translocation of sterol regulatory element-binding proteins (SREBPs), in particular SREBP-2, an activator of cholesterol synthesis in liver and a...

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PAQR3 modulates cholesterol homeostasis by anchoring Scap/SREBP complex to the Golgi apparatus

Cited by 70 publications

References 41 publications

Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1

Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1

A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP‐2

Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation

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