Cholesterol Metabolism: A Potential Therapeutic Target in Glioblastoma

Abstract

Glioblastoma is a highly lethal adult brain tumor with no effective treatments. In this review, we discuss the potential to target cholesterol metabolism as a new strategy for treating glioblastomas. Twenty percent of cholesterol in the body is in the brain, yet the brain is unique among organs in that it has no access to dietary cholesterol and must synthesize it de novo. This suggests that therapies targeting cholesterol synthesis in brain tumors might render their effects without compromising cell viability in other organs. We will describe cholesterol synthesis and homeostatic feedback pathways in normal brain and brain tumors, as well as various strategies for targeting these pathways for therapeutic intervention.

Keywords: blood–brain barrier; brain; cholesterol; glioblastoma; liver; liver X receptor (LXR); low-density lipoprotein receptor (LDLR); metabolism; sterol regulatory element binding protein (SREBP).

Figure 1

Cholesterol homeostasis in normal cells. Cells obtain cholesterol primarily through one of two mechanisms: (1) by synthesizing it de novo from acetyl CoA generated from glycolysis and (2) through exogenous uptake by low density lipoprotein receptors (LDLR). Cholesterol can negatively regulate its own levels through (3) the inhibition of proteolytic processing and nuclear import of sterol regulatory element binding proteins (SREBP2), leading to a decrease in activity in the mevalonate pathway or (4) through its conversion to oxysterols that activate liver X receptors (LXRs). LXRs lower cellular cholesterol levels by (5) inducing the transcription of the E3 ubiquitin ligase, IDOL, which ubiquitinates LDLR, and (6) by upregulating expression of the cholesterol efflux pump, ABCA1. SCAP: SREBP cleavage-activating protein; ER: endoplasmic reticulum.

Figure 2

Cholesterol metabolism in liver vs. brain. The brain obtains cholesterol exclusively from de novo synthesis. On the contrary, hepatic cholesterol can be obtained by de novo synthesis and through dietary intake. Dietary cholesterol can be esterified and loaded into chylomicrons in the intestine. The chylomicrons are released into circulation and hydrolyzed by lipoprotein lipase (LPL) to form chylomicron remnants. Cholesterol left behind in the chylomicron remnants are taken up and utilized in the liver. The cholesterol synthesized in liver and from dietary origins can be packed into very low-density lipoprotein (VLDL) and exported from liver. Cholesterol can also be oxidized in the liver to form bile acids which excreted from liver into the bile via the ABCB11 transporter. Cholesterol in the brain can be hydrolyzed to form hydroxycholesterol which crosses the blood–brain barrier (BBB) and goes to the liver to be converted to bile acid. Cholesterol in the liver can be recycled through enterohepatic circulation, which does not exist in the brain. About 5% of the bile acids are lost in the feces, and the rest are reabsorbed into enterocytes.

Figure 3

Cholesterol homeostasis in glioblastoma cells. Glioblastoma cells maintain cholesterol under conditions in which normal cells turn it off through multiple mechanisms of dysregulation (highlighted in red). They keep cholesterol biosynthesis on by constitutive activation of the mevalonate pathway (1), and by upregulating SREBPs under hypoxia (2). They are also highly dependent on appropriate levels of LXR activity—hyperactivating LXR with synthetic agonists overstimulates ABCA1 expression and cholesterol efflux, killing glioblastoma (GBM cells) (3). In sum, this provides them with cholesterol in an organ that is blocked from obtaining it from the circulation due to the blood-brain barrier.