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

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 could 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, 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 (SREBPs) that are responsable for the maintenance of cholesterol homeostasis through an intricated mechanism of regulation. Cholesterol obtained by hepatic de novo synthesis could be esterified and incorporated into apolipoprotein B (ApoB)-100-containing very low density lipoproteins (VLDL), 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 HDLs particles are internalized in the liver interacting with the hepatic scavenger receptor (SR-B1). Here we provide an updated overview on liver cholesterol metabolism regulation and deregulation and on the causes of cholesterol metabolism-related diseases. Moreover, current pharmacological treatment and novel hypocholesterolemic strategies will also be introduced.