Cholesterol metabolism during cell growth: Which role for the plasma membrane?

Abstract

Parenchyma proliferation is accompanied by a peculiar modification of the cholesterol metabolism involving both the growing tissue and the plasma compartment. The increase of cholesterol synthesis and uptake has been largely described in the literature and mainly ascribed to the increased requirement of cholesterol for new membrane biogenesis. The dramatic reduction of cholesterol efflux, which probably contributes to the increase of cholesterol esterification and accumulation, has also been largely described, although, further to acting as a prompt pool for membrane biogenesis requirements, its significance and possible influence on cholesterol homeostasis during growth has been almost completely neglected. In this short review, the most widely known modifications and new insights into the cholesterol metabolism during the growth of normal and tumoral cells will be discussed. Particular attention will be paid to the most widely known modifications of cholesterol storage and efflux. The possible implication of proteins in membrane cholesterol translocation causing cholesterol to be directed towards the ER for esterification by ACAT rather than being released by the appropriate external acceptor, i.e. HDL, during proliferation will be discussed. Keywords:Membrane cholesterol, HDL-C, cell proliferation, signal transduction. Cholesterol metabolism in non-growing cellsWith the exception of specialised cells such as hepatocytes, the majority of resting cells synthesise cholesterol only virtually, with the minimal amounts of the required sterols being obtained by an external source (via lowdensity lipoprotein (LDL) receptor), intracellular cholesterol esterification and efflux also being absent, in accordance with the low membrane turnover present in this condition. Under normal conditions, intracellular cholesterol homeostasis utilises a complex network of reactions capable of providing an adequate supply of cholesterol while avoiding possible conditions of toxicity for the cells. In the majority of cells, the cholesterol supply is regulated by the balance between endogenous synthesis in the endoplasmic reticulum (ER), under the control of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA-R), and uptake of exogenous cholesterol, involving endocytosis of the LDL receptor (LDL-r) complex [1]. Toxic conditions produced by excess free cholesterol can be avoided in several ways: by down-regulating cholesterol synthesis and uptake, by promoting esterification by acyl-CoA:cholesterol acyltransferase (ACAT) in the ER [2], and/or by transport to the plasma membrane with subsequent delivery to an external acceptor, i.e. highdensity lipoproteins (HDL) [3].However, it is a well-established fact that a pool of cholesterol completes a cycle to the membrane and returns to the ER with a half-time of 40 min [4], and numerous studies have been undertaken to clarify the mechanisms and the proteins involved in the transport of such a highly hydrophobic lipid between the various intracellular compartments [5][6][7].With regard to cholester...

A lipoprotein source of cholesteryl esters is essential for proliferation of CEM-CCRF lymphoblastic cell line

“…Gebhard [12] first reported that clear renal carcinoma in the rat contains 35-fold more CEs than the corresponding normal cells. Similar findings were also observed in the corresponding human renal cancer, as well as several experimental [13,14] and human tumours [1,2,15,16]. High levels of CEs are considered to be related to the large amounts of cholesterol needed by malignant cells to sustain membrane biogenesis.…”

“…On the other hand, this route has been reported to be essential for several functions, such as an optimal adrenal activity [47]. This novel mechanism, fundamental in maintaining high CE concentrations in tumour cells could account for the reduction of cholesterolemia, mainly c-HDL, described in experimental and human tumours [1][2][3]. Such a singular modification may be further supported by the reduction of cholesterol efflux observed mainly in cultured proliferating cells [18].…”

“…Moreover low levels of cholesterol-low-density lipoprotein (LDL) and cholesterol-high-density lipoprotein (HDL) have frequently been reported in cancer patients [4][5][6][7][8]. The authors previously hypothesised that during proliferative burst, the excess of membrane cholesterol is preferentially diverted to ER for esterification rather than delivered to HDL, this shift consequently increases intracellular CE and decreases it in the plasma compartment [1,2].…”

“…The cholesterol metabolism changes dramatically during tumour growth, being directed towards the uptake and storage of cholesterol in tumour tissues [1][2][3]. Moreover low levels of cholesterol-low-density lipoprotein (LDL) and cholesterol-high-density lipoprotein (HDL) have frequently been reported in cancer patients [4][5][6][7][8].…”

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

“…It is an integral component of all eukaryotic cell membranes and is essential for normal cellular function [51,52] . The decreased level of cholesterol both in the bile and in serum after VPA treatment further confirmed the deficiency of acetyl-CoA induced by VPA.…”