Cholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-rich domains called rafts and caveolae. Cholesterol is also a substrate for steroid hormones. However, too much cholesterol can lead to pathological pictures such as atherosclerosis, which is a consequence of the accumulation of cholesterol into the cells of the artery wall. The liver is considered to be the metabolic power station of mammalians, where cholesterol homeostasis relies on an intricate network of cellular processes whose deregulations can lead to several life-threatening pathologies, such as familial and age-related hypercholesterolemia. Cholesterol homeostasis maintenance is carried out by: biosynthesis, via 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity; uptake, through low density lipoprotein receptors (LDLr); lipoprotein release in the blood; storage by esterification; and degradation and conversion into bile acids. Both HMGR and LDLr are transcribed as a function of cellular sterol amount by a family of transcription factors called sterol regulatory element binding proteins that are responsible for the maintenance of cholesterol homeostasis through an intricate mechanism of regulation. Cholesterol obtained by hepatic de novo synthesis can be esterified and incorporated into apolipoprotein B-100-containing very low density lipoproteins, which are then secreted into the bloodstream for transport to peripheral tissues. Moreover, dietary cholesterol is transferred from the intestine to the liver by high density lipoproteins (HDLs); all HDL particles are internalized in the liver, interacting with the hepatic scavenger receptor (SR-B1). Here we provide an updated overview of liver cholesterol metabolism regulation and deregulation and the causes of cholesterol metabolism-related diseases. Moreover, current pharmacological treatment and novel hypocholesterolemic strategies will also be introduced.

Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic “power station”

Although statins, 3β-hydroxy-3β-methylglutaryl coenzyme A reductase (HMGR) inhibitors, have revolutionized the management of cardiovascular diseases by lowering serum low density lipoproteins, many patients suffer from their side effects. Whether the statin side effects are related to their intrinsic toxicity or to the decrease of HMGR main isoprenoid end products, which are essential compounds for cell viability, is still debated. In addition to HMGR, the key and rate limiting step of cholesterol synthesis, many enzymes are involved in this multi-step pathway whose inhibition could be taken into account for a "nonstatin approach" in the management of hypercholesterolemia. In particular, due to their unique position downstream from HMGR, the inhibition of squalene synthase, farnesyl diphosphate farnesyltransferase (FDFT1), squalene epoxidase (SQLE), and oxidosqualene cyclase:lanosterol synthase (OSC) should decrease plasma levels of cholesterol without affecting ubiquinone, dolichol, and isoprenoid metabolism. Thus, although FDFT1, SQLE and OSC are little studied, they should be considered as perspective targets for the development of novel drugs against hypercholesterolemia. Here, structure-function relationships of FDFT1, SQLE, and OSC are reviewed highlighting the advantages that the downstream inhibition of HMGR could provide when compared to the statin-based therapy.

https://iubmb.onlinelibrary.wiley.com/doi/pdf/10.1002/iub.522

Potential role of nonstatin cholesterol lowering agents

https://www.vp-scientific.com/reference-pdf/Chemistry%20&%20Biology-2011-Wallace.pdf

Compound Prioritization Methods Increase Rates of Chemical Probe Discovery in Model Organisms

Novel pyrrole- and 1,2,3-triazole-based 2,3-oxidosqualene cyclase inhibitors.

Small molecules, both dietary and endogenous, influence the onset of lens cataracts.

Design and evaluation of a novel series of 2,3-oxidosqualene cyclase inhibitors with low systemic exposure, relationship between pharmacokinetic properties and ocular toxicity

Sylvie Demaria Magny

Papers

Design and evaluation of a novel series of 2,3-oxidosqualene cyclase inhibitors with low systemic exposure, relationship between pharmacokinetic properties and ocular toxicity