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肝内 PCSK9 基因表达上调和 LDL 受体水平降低可能是脂肪切除术后高胆固醇血症的原因。

Up-regulation of PCSK9 gene expression and diminished level of LDL-receptor in rat liver as a potential cause of post-lipectomy hypercholesterolemia.

机构信息

Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland.

Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdansk, ul. Debinki 7, 80-211, Gdansk, Poland.

出版信息

Mol Cell Biochem. 2019 May;455(1-2):207-217. doi: 10.1007/s11010-018-3484-8. Epub 2018 Nov 27.

Abstract

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.

摘要

旨在研究脂肪质量减少(包括脂肪营养不良和脂肪切除术)对人体血清总胆固醇和 LDL-胆固醇浓度影响的研究结果并不一致。本研究的目的是研究大鼠部分脂肪切除术(作为人类脂肪质量减少的实验模型)对(1)循环总胆固醇、LDL-胆固醇+VLDL-胆固醇和 HDL-胆固醇浓度,以及(2)可能影响血清胆固醇浓度的因素的影响,如:(a)肝脏 LDL 受体水平,(b)肝脏 PCSK9 表达和(c)循环 PCSK9 浓度的影响。减少大鼠脂肪组织质量导致循环总胆固醇和 LDL+VLDL-胆固醇浓度升高,这与(a)肝脏 LDL-R 水平降低,(b)肝脏 PCSK9 表达增加,(c)与假手术对照组相比,循环 PCSK9 浓度增加有关。这些变化伴随着肝 HNF1α(和 HNF4α)mRNA 水平升高。用 siRNA 沉默 HepG2 细胞中的 HNF1α 导致 PCSK9 mRNA 水平降低。这表明,脂肪切除术大鼠肝脏中 HNF1α 基因的过度表达可导致 PCSK9 的过度产生。总之,由于脂肪切除术大鼠肝脏中 HNF1α 基因的过度表达导致 PCSK9 的上调,继而导致循环 PCSK9 浓度升高,导致肝脏 LDL-R 水平降低。这可能至少部分导致脂肪质量减少的大鼠循环胆固醇浓度升高。这些发现为人类脂肪质量减少时观察到的高胆固醇血症的分子机制提供了可能的解释。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/056c/6445806/c010bc1c64a3/11010_2018_3484_Fig1_HTML.jpg

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