Cholesterol metabolism in the regulation of inflammatory responses

Abstract

The importance of biologically active lipid mediators, such as prostanoids, leukotrienes, and specialized pro-resolving mediators, in the regulation of inflammation is well established. While the relevance of cholesterol in the context of atherosclerosis is also widely accepted, the role of cholesterol and its biosynthetic precursors on inflammatory processes is less comprehensively described. In the present mini-review, we summarize the current understanding of the inflammation-regulatory properties of cholesterol and relevant biosynthetic intermediates taking into account the implications of different subcellular distributions. Finally, we discuss the inflammation-regulatory effect of cholesterol homeostasis in the context of SARS-CoV-2 infections.

Keywords: COVID-19; SARS-CoV-2; cholesterol; immunometabolism; inflammation.

FIGURE 1

Cholesterol homeostasis and inflammatory regulation. 1. Uptake: Cholesterol is taken up bound to low-density lipoprotein (LDL) particles via LDL-receptor (LDL-R)-associated endocytosis, released from LDL upon fusion of endosomes with lysosomes, and distributed by Niemann-Pick type C (NPC) proteins to either the endoplasmic reticulum (ER) or the plasma membrane. 2. Biosynthesis: Cholesterol is synthesized starting from acetyl-CoA in the cytoplasm, converted via 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate in the ER, further processed in peroxisomes to the isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which can also be produced from the GGPP-precursor geranylgeraniol (GGOH). In the ER, two FPP molecules condensate to squalene, which in a multi-step process is processed to lanosterol, which is further metabolized in the parallel Bloch and Kandutsch-Russel (K-R) pathways to desmosterol and 7-dehydrocholesterol (7-DHC), respectively, both of which are direct precursors of cholesterol. ER cholesterol levels are sensed by sterol response element-binding protein 2 (SREBP2), which is bound by SREBP cleavage-activating protein (SCAP) and insulin-induced gene (INSIG) in the ER. Low ER cholesterol levels induce translocation of SCAP-bound SREBP2 to the Golgi, where it undergoes cleavage-dependent activation. The N-terminal SREBP2 fragment acts as transcription factor among others for cholesterol biosynthesis enzymes and LDL-R. 3. Efflux: Excess cholesterol in the ER is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT) and subsequently either stored in lipid droplets or exported via ATP-binding cassette A1 (ABCA1) or ABCG1 and loaded onto high-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) for retrograde transport to the liver. Elevated oxysterol and desmosterol levels further activate the transcription factor liver X receptor (LXR) to enhance the expression of cholesterol exporters.