Tumor necrosis factor up-regulates expression of low-density lipoprotein receptors on HepG2 cells

Abstract

Tumor necrosis factor mediates most biological activities of endotoxin and also, in part, mediates endotoxin-induced disturbances in lipid metabolism. In this study, the effect of tumor necrosis factor on low-density lipoprotein receptor activity was investigated in cells of HepG2, a well-differentiated human hepatoma cell line. Pretreatment of the cells with tumor necrosis factor leads to enhanced binding, uptake and degradation of 125I-labeled low-density lipoprotein. This effect of tumor necrosis factor was dose and time dependent. Tumor necrosis factor-stimulated enhancement of low-density lipoprotein binding occurred at all stages of cell growth. However, addition of an excess of unlabeled low-density lipoprotein, to down-regulate low-density lipoprotein receptors before exposure to tumor necrosis factor of the cells, completely abolished the effects of tumor necrosis factor. Competition experiments using unlabeled low-density lipoprotein and blockage experiments with a monoclonal low-density lipoprotein receptor antibody showed that tumor necrosis factor-stimulated low-density lipoprotein binding takes place through stimulation of low-density lipoprotein receptors. Comparison of the kinetics of specific low-density lipoprotein binding in the unstimulated cells and in the tumor necrosis factor-stimulated cells indicated that tumor necrosis factor caused a 30% increase in maximum velocity with no significant change in Michaelis constant, suggesting that tumor necrosis factor increases the number of low-density lipoprotein receptors on the cells rather than changing binding affinity. Preincubation of the cells with cycloheximide or actinomycin D totally abolished the up-regulatory effect of tumor necrosis factor on low-density lipoprotein receptors. Tumor necrosis factor did not stimulate proliferation of HepG2 cells, as judged by cell protein determination or by [3H]thymidine incorporation. In conclusion, this study suggests that tumor necrosis factor up-regulates expression of low-density lipoprotein receptors on HepG2 cells by stimulation of de novo synthesis of receptors, independent of cell growth.

Endotoxin suppresses rat hepatic: Low density lipoprotein receptor expression

“…These cytokines induce hyperlipidaemia (reviewed in [18,19]). However, tumour necrosis factor, interleukins 1 and 6, and oncostatin M have been shown to stimulate LDL receptor expression in cultured hepatocytes [38][39][40][41] and other cells [42,43]. Endotoxin also induces release of hormones such as catecholamines and glucocorticoids.…”

Soluble LDL‐R are formed by cell surface cleavage in response to phorbol esters

“…The LDL‐R plays an important role in regulating plasma LDL and cellular cholesterol levels and the activity of this receptor has a direct bearing on plasma cholesterol levels. The LDL receptor is regulated at the transcriptional level in response to intracellular sterol levels by means of sterol sensitive transcription factors SREBP1 and SREBP2 [2,3], however, it can also be upregulated by numerous cytokines [tumor necrosis factor (TNF)‐α, interleukin (IL)‐1, transforming growth factor (TGF)‐β, oncostatin M, platelet‐derived growth factor and basic fibroblast growth factor (bFGF) [4–8], hormones (insulin and estradiol) [9,10] and second messenger systems [11,12]. Although much is known about the transcriptional mechanisms that control LDL‐R expression, little is known about the mechanism(s) that control the turnover and degradation of this important protein.…”

HDL in COVID-19 Patients: Evidence from an Italian Cross-Sectional Study

“…Relative to cholesterol metabolism, the inflammatory storm associated to infection decreases serum cholesterol as a result of a decrement in LDL-c. This is possibly due to an increase in the expression and activity of the LDL receptor and increased in LDL catabolism [28,29].…”