The Role of Cholesterol in Chronic Lymphocytic Leukemia Development and Pathogenesis

Figures

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  Figure 1. Cholesterol synthesis and trafficking in various tissues. The exogenous pathway begins with the uptake of dietary cholesterol where lipids are incorporated into chylomicrons in the intestine. Once in the circulation, the chylomicrons are metabolized by tissues that contain lipoprotein lipase (LPL), and their contents, free fatty acids (FFA) and glycerol, are metabolized by tissues such as muscle and adipose tissue. In muscle, FFAs are used for energy. In the adipose tissue, they can be stored in the form of triglycerides (TG). The resulting chylomicron remnants in the circulation are absorbed in the liver by apolipoprotein-specific receptors (VLDLR and LDLR). The endogenous pathway begins in the liver with the formation of cholesterol from acetyl-CoA, catalyzed by the enzyme HMG-CoA reductase. The VLDL particles, containing triglycerides and cholesterol esters, can be hydrolyzed by LPL to form IDL with the release of FFAs. IDLs can further be hydrolyzed to LDLs by the action of hepatic lipase (HL), which also results in the release of FFAs. LDL can be internalized by other tissues, such as the liver by the LDL receptor (LDLR).

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  Figure 2. The high-affinity HDL receptor, SR-B1, is overexpressed on CLL cells, which leads to an increased uptake of HDL-derived cholesterol esters and the diffusion of free cholesterol (FC) into the plasma membrane and cytoplasm. As cytoplasmic FC is toxic, it undergoes esterification by acyl-coenzyme-1 (ACAT-1) to protect the cells from ER stress and apoptosis. Cholesterol esters (CE) represent a safe way to store intracellular cholesterol and act as a repository, which can be exploited by the cancers cells to fuel rapid proliferation by lysosomal acid lipase (LAL) degradation of CE to free fatty acids (FFA) and FC.

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  Figure 3. The sterol regulatory element-binding protein transcription factor 2 (SREBP2) pathway regulates endogenous cholesterol synthesis. Cholesterol levels in the endoplasmic reticulum (ER) act as a sensor for intracellular cholesterol homeostasis. When high-intracellular cholesterol levels are detected, SREBP2 remains in the ER, resulting in a decreased expression of HMG–CoA reductase (HMGCR). HMG–CoA also undergoes proteasomal degradation, further reducing its activity. When cholesterol levels in the ER decrease, SREBP2 translocates to the nucleus and activates the transcription of genes, including HMGCR, which regulates the expression of HMG–CoA reductase and the LDL receptor (LDLR), resulting in an increase in cholesterol uptake into the cell.

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  Figure 4. Targeting cholesterol biosynthesis or hydrolysis in CLL. There are two key enzymes in the biosynthesis of cholesterol, HMG–CoA reductase (HMGCR), and squalene synthase, which can be targeted by a range of inhibitors such as statins, YM-53601, and lapaquistat. As cholesterol is essential for membranes and as a precursor for cholesterol esters and other factors, disrupting the biosynthesis pathway is an attractive treatment option in CLL. On the other hand, triglycerides (TG) and cholesterol (C) can directly enter the cell via endosomes and be hydrolyzed by lipases. The resulting free fatty acids (FFAs) and free cholesterol (FC) can have downstream effects that promote the growth and survival of the CLL cells, such as altering the expression of transcriptional regulators, such as STAT3 or by increasing the lipid content of the membrane, leading to altered cellular functions, such as increased activation of oncogenic pathways and trafficking. Orlistat and lalistat are two inhibitors that have been investigated in CLL due to their ability to block lipases and prevent the hydrolysis of cholesterol and triacylglycerols.