Cholesterol metabolism pathway

Cholesterol and its metabolites are pivotal in cellular and systemic functions. The regulation of cholesterol metabolism in humans is a highly intricate process maintained through a dynamic balance of synthesis, uptake, efflux, and storage. Disruption of any of these processes can negatively impact the body¹.

Primarily located on the cell membrane, cholesterol interacts with adjacent lipids, regulating the bilayer's rigidity, fluidity, and permeability. Moreover, cholesterol can bind to numerous transmembrane proteins, facilitating the maintenance or alteration of their conformation. In addition to its role in the membrane structure and function, cholesterol generates diverse oxysterols through enzymatic and nonenzymatic pathways, with some subsequently metabolized into bile acids. Its transportation to the mitochondria is crucial for synthesizing oxysterols and steroids. The steroidogenic acute regulatory protein (StAR) facilitates cholesterol delivery to the inner mitochondrial membrane. This process is vital for regulating oxidative stress responses implicated in diseases like cancer and Alzheimer's.

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In mammalian cells, cholesterol can be synthesized from acetate precursors (de novo synthesis) or taken up from dietary or exogenous sources (systemic circulation). Cholesterol de novo synthesis starts with acetyl-CoA, which is converted into mevalonate by the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). This enzyme is a key rate-limiting step in the cholesterol synthesis process. For example, statins inhibit cholesterol synthesis in the liver by blocking HMGCR. Following this, mevalonate is transformed into squalene and further converted into lanosterol. Cholesterol biosynthesis is divided into the Bloch and Kandutsch–Russell pathways. In the Bloch pathway, lanosterol goes through five steps to produce desmosterol. Meanwhile, in the Kandutsch–Russell pathway, lanosterol also experiences five steps but forms 7-dehydrodesmosterol. The final stages in both pathways involve the enzymes 24-dehydroxysterol reductase (DHCR24) and 7-dehydroxysterol reductase (DHCR7), which catalyze the conversion of desmosterol and 7-dehydrodesmosterol into cholesterol².

The transportation of cholesterol in the blood depends on its association with lipoproteins due to its insolubility. In systemic circulation, lipoproteins are classified into five types based on their densities: chylomicrons (CM), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The epithelial cells of the intestine can absorb cholesterol from dietary sources through the Niemann‐Pick type C1‐like 1 protein (NPC1L1), releasing exogenous cholesterol in CM. These chylomicrons are then transported to the liver via the bloodstream and converted into VLDL. The primary role of VLDL is to transport endogenous cholesterol. Eventually, VLDL is transformed into LDL in the blood, which distributes cholesterol throughout the body. The low-density lipoprotein receptor (LDLR) is a glycoprotein on cell surfaces that plays a critical role in the cholesterol uptake of peripheral cells from systemic circulation. In addition, when cellular cholesterol levels are low, the SREBP2 transcription factor translocates to the nucleus. It increases the expression of the LDLR, which enhances the uptake of LDL cholesterol from the bloodstream. Moreover, SREBP2 also upregulates the expression of the HMGCR gene, leading to increased cholesterol de novo synthesis when cellular levels are low.

To preserve cholesterol homeostasis in cells, excess cholesterol must be removed, transported to the liver through the blood, metabolized, and ultimately excreted. This process is known as reverse cholesterol transport (RCT). Cholesterol efflux from cells is the initial step of the RCT, where liver X receptors (LXRs) and the transporters ABCA1 and ABCG1 serve as key regulators, playing a vital role in this activity³.

Cholesterol metabolism is a complex process that depends on the orchestrated arrangement of several steps and is regulated by multiple signaling pathways throughout the body.

References

1. Guo, J. et al. Cholesterol metabolism: physiological regulation and diseases. MedComm 5, e476 (2024).

2. Sharpe, L. J., Coates, H. W. & Brown, A. J. Post-translational control of the long and winding road to cholesterol.  J. Biol. Chem.  295, 17549–17559 (2020).

3. Tall, A. R. An overview of reverse cholesterol transport.  Eur. Heart J.  19A, A31–A35 (1998).