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.
Highlights
Liposuction is popular esthetic surgery to remove significant amount of subcutaneous adipose tissue within a short period of time, recommended by the American Academy of Cosmetic Surgery [1]
The aim of this study was to verify if an increase in HNF1α and HNF4α gene expression in the liver is associated with activation of proprotein convertase subtilisin/kexin 9 (PCSK9) production, which through degradation of LDL-R may lead to increase in serum cholesterol concentrations in lipectomized rats
PCSK9 is a serine protease synthesized and released mainly by liver, which binds to LDL-R on the surface of hepatocyte, forming a complex that is internalized and degraded [46]
Summary
Liposuction is popular esthetic surgery to remove significant amount of subcutaneous adipose tissue within a short period of time, recommended by the American Academy of Cosmetic Surgery [1]. The metabolic consequences of liposuction or abdominal lipectomy, especially changes in serum lipids concentrations, are still controversial [2]. The results of previous studies performed in humans have shown: (a) no change [3,4,5,6,7], (b) decrease [8,9,10,11], or (c) increase [12] in one or few cardiovascular risk factors including dyslipidemia. Further studies are needed to clarify the effect of fat loss on lipid metabolism at the molecular level. It seems that, the lipectomy model offers some insight into how fat mass reduction may affect hypercholesterolemia sometimes observed in individuals after weight loss
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