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

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.

Gentianella acuta mitigates cardiovascular damage and inflammation in diet‑induced hypercholesterolaemic rats

“…These histopathological changes in the body were important formative indices of hypercholesterolaemia, with some beneficial changes appearing in the Model-G group, such as improved aortic wall structure and neatly arranged myocardial cells. Lipid deposition has been identified as an important cause of AS, which can lead to the increase of free radicals, thereby damaging endothelial cell function (30)(31)(32). Thus, the release of protective factors is reduced, leading to a reduction in the tightness of endothelial cells and increased permeability, which in turn results in increased lipid deposition, forming a vicious circle (33).…”

Effect of Sleeve Gastrectomy on Proprotein Convertase Subtilisin/Kexin Type 9 (Pcsk9) Content and Lipid Metabolism in the Blood Plasma and Liver of Obese Wistar Rats

“…This made the SG rats similar to the control group, at least with respect to the PCSK9 protein level. Interestingly, a study by Dettlaff-Pokora et al [34] indicated that a partial surgical removal of adipose tissue (i.e., white adipose tissue (WAT)) in rats may cause an upregulation of liver PCSK9-encoding genes. This probably contributed to an elevated level of circulating PCSK9 and a decrease in the liver LDLR expression.…”