Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9)
Abstract Background PCSK9 regulates low-density lipoprotein cholesterol (LDLc) level and has been implicated in hypercholesterolemia. Aberrant plasma lipid profile is often associated with various cancers. Clinically, the relationship between altered serum lipid level and hepatocellular carcinoma (H...
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BMC
2018-10-01
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| Series: | Cancer & Metabolism |
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| Online Access: | http://link.springer.com/article/10.1186/s40170-018-0187-2 |
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| author | Dipti Athavale Surbhi Chouhan Vimal Pandey Shyamananda Singh Mayengbam Snahlata Singh Manoj Kumar Bhat |
| author_facet | Dipti Athavale Surbhi Chouhan Vimal Pandey Shyamananda Singh Mayengbam Snahlata Singh Manoj Kumar Bhat |
| author_sort | Dipti Athavale |
| collection | DOAJ |
| description | Abstract Background PCSK9 regulates low-density lipoprotein cholesterol (LDLc) level and has been implicated in hypercholesterolemia. Aberrant plasma lipid profile is often associated with various cancers. Clinically, the relationship between altered serum lipid level and hepatocellular carcinoma (HCC) has been documented; however, the underlying cause and implications of such dyslipidemia remain unclear. Methods The present study includes the use of HepG2 tumor xenograft model to study the potential role of glucose (by providing 15% glucose via drinking water) in regulating PCSK9 expression and associated hypercholesterolemia. To support in vivo findings, in vitro approaches were used by incubating HCC cells in culture medium with different glucose concentrations or treating the cells with glucose uptake inhibitors. Impact of hypercholesterolemia on chemotherapy was demonstrated by exogenously providing LDLc followed by appropriate in vitro assays. Results We observed that serum and hepatic PCSK9 level is decreased in mice which were provided with glucose containing water. Interestingly, serum and tumor PCSK9 level was upregulated in HepG2-tumor-bearing mice having access to water containing glucose. Additionally, elevated LDLc is detected in sera of these mice. In vitro studies indicated that PCSK9 expression was increased by high glucose availability with potential involvement of reactive oxygen species (ROS) and sterol regulatory element binding protein-1 (SREBP-1). Furthermore, it is also demonstrated that pre-treatment of cells with LDLc diminishes cytotoxicity of sorafenib in HCC cells. Conclusion Taken together, these results suggest a regulation of PCSK9 by high glucose which could contribute, at least partly, towards understanding the cause of hypercholesterolemia in HCC and its accompanied upshots in terms of altered response of HCC cells towards cancer therapy. |
| first_indexed | 2024-12-14T20:05:22Z |
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| language | English |
| last_indexed | 2024-12-14T20:05:22Z |
| publishDate | 2018-10-01 |
| publisher | BMC |
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| series | Cancer & Metabolism |
| spelling | doaj.art-14605acedb8141b393b5e4e26598e3292022-12-21T22:49:03ZengBMCCancer & Metabolism2049-30022018-10-016111610.1186/s40170-018-0187-2Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9)Dipti Athavale0Surbhi Chouhan1Vimal Pandey2Shyamananda Singh Mayengbam3Snahlata Singh4Manoj Kumar Bhat5Laboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University CampusLaboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University CampusLaboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University CampusLaboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University CampusLaboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University CampusLaboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University CampusAbstract Background PCSK9 regulates low-density lipoprotein cholesterol (LDLc) level and has been implicated in hypercholesterolemia. Aberrant plasma lipid profile is often associated with various cancers. Clinically, the relationship between altered serum lipid level and hepatocellular carcinoma (HCC) has been documented; however, the underlying cause and implications of such dyslipidemia remain unclear. Methods The present study includes the use of HepG2 tumor xenograft model to study the potential role of glucose (by providing 15% glucose via drinking water) in regulating PCSK9 expression and associated hypercholesterolemia. To support in vivo findings, in vitro approaches were used by incubating HCC cells in culture medium with different glucose concentrations or treating the cells with glucose uptake inhibitors. Impact of hypercholesterolemia on chemotherapy was demonstrated by exogenously providing LDLc followed by appropriate in vitro assays. Results We observed that serum and hepatic PCSK9 level is decreased in mice which were provided with glucose containing water. Interestingly, serum and tumor PCSK9 level was upregulated in HepG2-tumor-bearing mice having access to water containing glucose. Additionally, elevated LDLc is detected in sera of these mice. In vitro studies indicated that PCSK9 expression was increased by high glucose availability with potential involvement of reactive oxygen species (ROS) and sterol regulatory element binding protein-1 (SREBP-1). Furthermore, it is also demonstrated that pre-treatment of cells with LDLc diminishes cytotoxicity of sorafenib in HCC cells. Conclusion Taken together, these results suggest a regulation of PCSK9 by high glucose which could contribute, at least partly, towards understanding the cause of hypercholesterolemia in HCC and its accompanied upshots in terms of altered response of HCC cells towards cancer therapy.http://link.springer.com/article/10.1186/s40170-018-0187-2Hepatocellular carcinomaHypercholesterolemiaGlucosePCSK9Sorafenib |
| spellingShingle | Dipti Athavale Surbhi Chouhan Vimal Pandey Shyamananda Singh Mayengbam Snahlata Singh Manoj Kumar Bhat Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9) Cancer & Metabolism Hepatocellular carcinoma Hypercholesterolemia Glucose PCSK9 Sorafenib |
| title | Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9) |
| title_full | Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9) |
| title_fullStr | Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9) |
| title_full_unstemmed | Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9) |
| title_short | Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9) |
| title_sort | hepatocellular carcinoma associated hypercholesterolemia involvement of proprotein convertase subtilisin kexin type 9 pcsk9 |
| topic | Hepatocellular carcinoma Hypercholesterolemia Glucose PCSK9 Sorafenib |
| url | http://link.springer.com/article/10.1186/s40170-018-0187-2 |
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