Up-regulation of PCSK9 gene expression and diminished level of LDL-receptor in rat liver as a potential cause of post-lipectomy hypercholesterolemia
| Autor: | Tomasz Sledzinski, Agnieszka Dettlaff-Pokora, Elzbieta Sucajtys-Szulc |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Clinical chemistry Hypercholesterolemia Clinical Biochemistry Adipose tissue LDL-R Article Gene Expression Regulation Enzymologic PCSK9 03 medical and health sciences PCSK9 Gene chemistry.chemical_compound Postoperative Complications 0302 clinical medicine Lipectomy Downregulation and upregulation Internal medicine medicine Animals Rats Wistar Molecular Biology Chemistry Cholesterol Cell Biology General Medicine medicine.disease Rats Up-Regulation 030104 developmental biology Endocrinology Liver Receptors LDL 030220 oncology & carcinogenesis LDL receptor lipids (amino acids peptides and proteins) Proprotein Convertase 9 Lipodystrophy HNF1α |
| Zdroj: | Molecular and Cellular Biochemistry |
| ISSN: | 1573-4919 0300-8177 |
| DOI: | 10.1007/s11010-018-3484-8 |
| Popis: | Studies designed to examine effects of fat mass reduction (including lipodystrophy and lipectomy) on human serum total and LDL-cholesterol concentrations are inconsistent. The purpose of this study was to examine effect of partial lipectomy in rats (as an experimental model of fat mass reduction in humans) on (1) circulating total cholesterol, LDL-cholesterol + VLDL-cholesterol and HDL-cholesterol concentrations, and (2) factors which may affect serum cholesterol concentrations such as: (a) liver LDL-receptor level, (b) expression of liver PCSK9 and (c) circulating PCSK9 concentration. Reduction of rat adipose tissue mass resulted in an increase in circulating total and LDL + VLDL-cholesterol concentrations, which was associated with (a) decrease in liver LDL-R level, (b) increase in liver PCSK9 expression, and (c) increase in circulating PCSK9 concentration as compared with sham controls. These changes were accompanied by elevated liver HNF1α (and HNF4α) mRNA levels. Silencing HNF1α in HepG2 cells by siRNA led to decrease in PCSK9 mRNA levels. This suggests that overexpression of HNF1α gene in liver of lipectomized rats can lead to overproduction of PCSK9. In conclusion, up-regulation of PCSK9, due to overexpression of HNF1α gene in liver of lipectomized rats and subsequently increase in circulating PCSK9 concentration lead to decrease in liver LDL-R level. This may contribute, at least in part, to an increase in the concentration of circulating cholesterol in rats with reduced fat mass. These findings provide a possible explanation for the molecular mechanism of hypercholesterolemia observed sometimes after reduction of fat mass in human. |
| Databáze: | OpenAIRE |
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