Overexpression of A-kinase anchoring protein 12A activates sterol regulatory element binding protein-2 and enhances cholesterol efflux in hepatic cells

Choi, Myeon-Song; Lee, Yang Ui; Kim, Sung Hak; Park, Jung Hyun; Streb, Jeffrey W.; Oh, Do‐Youn; Im, Seock‐Ah; Kim, Taeyou; Jong, Hyun Soon; Bang, Yung Jue

doi:10.1016/j.biocel.2008.04.020

Cited by 7 publications

(6 citation statements)

References 55 publications

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“…We observed in gravin-t/t mice that gene expression of both LDLR and SREBP-2 were downregulated and that this gene expression was decreased irrespective of the ND or HFD diet. Relevant to our findings, Choi and colleagues (13) reported that gravin participates in cholesterol metabolism via SREBP-2 activation and that overexpression of gravin activates SREBP-2 in a SCAP-dependent manner. This is consistent with our results, in which we showed that gravin-t/t mice had decreased SREBP-2 gene expression, resulting in downregulation of HMGCR and LDLR and thus lower circulatory cholesterol levels.…”

Section: Discussionsupporting

confidence: 88%

“…AKAPs regulate cAMP-dependent PKA signaling events that control lipolysis (55), including the regulation of lipoprotein lipase (LPL) expression via the inhibition of its translation (53). Additionally, it has been previously reported that gravin mediates cellular lipid metabolism via inducing the activation of sterol regulatory element binding proteins (SREBPs) in hepatocytes, which are transcription factors that bind to the sterol regulatory element DNA sequence of cholesterol-associated genes (13).…”

Section: Introductionmentioning

confidence: 99%

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Absence of gravin-mediated signaling inhibits development of high-fat diet-induced hyperlipidemia and atherosclerosis

Fan

Yin

Rababa’h

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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Gravin, an A-kinase anchoring protein, is known to play a role in regulating key processes that lead to inflammation and atherosclerosis development, namely, cell migration, proliferation, and apoptosis. We investigated the role of gravin in the development of high-fat diet (HFD)-induced atherosclerosis and hyperlipidemia. Five-week-old male wild-type (WT) and gravin-t/t mice were fed a normal diet or an HFD for 16 wk. Gravin-t/t mice showed significantly lower liver-to-body-weight ratio, cholesterol, triglyceride, and very low-density lipoprotein levels in serum as compared with WT mice on HFD. Furthermore, there was less aortic plaque formation coupled with decreased lipid accumulation and liver damage, as the gravin-t/t mice had lower levels of serum alanine aminotransferase and aspartate aminotransferase. Additionally, gravin-t/t HFD-fed mice had decreased expression of liver 3-hydroxy-3-methyl-glutaryl-CoA reductase, an essential enzyme for cholesterol synthesis and lower fatty acid synthase expression. Gravin-t/t HFD-fed mice also exhibited inhibition of sterol regulatory element binding protein-2 (SREBP-2) expression, a liver transcription factor associated with the regulation of lipid transportation. In response to platelet-derived growth factor receptor treatment, gravin-t/t vascular smooth muscle cells exhibited lower intracellular calcium transients and decreased protein kinase A- and protein kinase C-dependent substrate phosphorylation, notably involving the Erk1/2 signaling pathway. Collectively, these results suggest the involvement of gravin-dependent regulation of lipid metabolism via the reduction of SREBP-2 expression. The absence of gravin-mediated signaling lowers blood pressure, reduces plaque formation in the aorta, and decreases lipid accumulation and damage in the liver of HFD mice. Through these processes, the absence of gravin-mediated signaling complex delays the HFD-induced hyperlipidemia and atherosclerosis. NEW & NOTEWORTHY The gravin scaffolding protein plays a key role in the multiple enzymatic pathways of lipid metabolism. We have shown for the first time the novel role of gravin in regulating the pathways related to the initiation and progression of atherosclerosis. Specifically, an absence of gravin-mediated signaling decreases the lipid levels (cholesterol, triglyceride, and VLDL) that are associated with sterol regulatory element binding protein-2 downregulation.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Absence of gravin-mediated signaling inhibits development of high-fat diet-induced hyperlipidemia and atherosclerosis

Fan

Yin

Rababa’h

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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“…A correlation of AKAP12 levels with cholesterol metabolism in hepatic cells has been previously reported 12. However, no study has been conducted on the possible perturbation of AKAP12 in real surgical HCC samples.…”

Section: Introductionmentioning

confidence: 91%

Identification of the a kinase anchor protein 12 (AKAP12) gene as a candidate tumor suppressor of hepatocellular carcinoma

Hayashi

Nomoto

Kanda

et al. 2011

Journal of Surgical Oncology

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“…Arp2/3 plays a role during actin polymerization near cellular membranes and mediates the transport of early endosomes toward late/mature endosomes. , Additionally, Arp2/3 can be regulated by Protein Kinase C delta to enclose F-actin around early endosomes, thus preventing the recycling of EGFR containing vesicles to the cell surface and thereby promoting EGFR degradation. , AKAP-12 is a scaffold protein that can promote the internalization, resensitization and recycling of the β-2-andrenergic receptor through calcium-dependent interactions . Additionally, its overexpression leads to a subsequent up-regulation of SREBP-2 activity (sterol regulatory element binding protein; a transcription factor involved in the regulation of genes important for cholesterol homeostasis) and increases cholesterol efflux from the cell . GAPDH, sometimes used as a “loading control” or “house keeping gene/protein”, was upregulated in subcellular fraction 3 representing endosomal/lysosomal enriched fractions.…”

Section: Resultsmentioning

confidence: 99%

“…70 Additionally, its overexpression leads to a subsequent up-regulation of SREBP-2 activity (sterol regulatory element binding protein; a transcription factor involved in the regulation of genes important for cholesterol homeostasis) and increases cholesterol efflux from the cell. 71 GAPDH, sometimes used as a "loading control" or "house keeping gene/protein", was upregulated in subcellular fraction 3 representing endosomal/lysosomal enriched fractions. This would reflect a small portion of total cell GAPDH and would not affect total cell levels.…”

Section: Trends In Clustered Data In Quantified Proteins Across Subce...mentioning

confidence: 99%

Quantitative Proteomic Analysis of PCSK9 Gain of Function in Human Hepatic HuH7 Cells

Denis¹,

Palmer-Smith²,

Elisma³

et al. 2011

J. Proteome Res.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in cholesterol homeostasis, mediating degradation of the liver low-density lipoprotein receptor (LDLR). In fact, gain- and loss-of-function PCSK9 variations in human populations associate with hyper- or hypo- cholesterolemia, respectively. Exactly how PCSK9 promotes degradation of the LDLR, the identity of the other biomolecules involved in this process, and the global effect of PCSK9 on other proteins has not been thoroughly studied. Here we employ stable isotope labeling with amino acids in cell culture (SILAC) to present the first quantitative, subcellular proteomic study of proteins affected by the stable overexpression of a gain-of-function PCSK9 membrane-bound chimera (PCSK9-V5-ACE2) in comparison to control, empty vector transfections in a human hepatocyte (HuH7) cell line. The expression level of 327 of 5790 peptides was modified by PCSK9-V5-ACE2 overexpression. Immunoblotting was carried out for the control transferrin receptor, shown to be unaffected in cells overexpressing PCSK9-V5-ACE2, thus validating our SILAC results. We also used immunoblotting to confirm the novel SILAC results of up- and down-regulation of several proteins in cells overexpressing PCSK9-V5-ACE2. Moreover, we documented the novel down-regulation of the EH domain binding protein-1 (EHBP1) in a transgenic PCSK9 mouse model and its up-regulation in a PCSK9 knockout mouse model.

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Overexpression of A-kinase anchoring protein 12A activates sterol regulatory element binding protein-2 and enhances cholesterol efflux in hepatic cells

Cited by 7 publications

References 55 publications

Absence of gravin-mediated signaling inhibits development of high-fat diet-induced hyperlipidemia and atherosclerosis

Absence of gravin-mediated signaling inhibits development of high-fat diet-induced hyperlipidemia and atherosclerosis

Identification of the a kinase anchor protein 12 (AKAP12) gene as a candidate tumor suppressor of hepatocellular carcinoma

Quantitative Proteomic Analysis of PCSK9 Gain of Function in Human Hepatic HuH7 Cells

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