Several mutations in the apolipoprotein (apo) B, microsomal triglyceride transfer protein (MTTP), and proprotein convertase subtilisin kexin 9 (PCSK9) genes result in low or absent levels of apoB and LDL-C in plasma which cause familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL). Familial combined hypolipidemia (FHBL2) results from mutations in the angiopoietin-like protein 3 (ANGPTL3) gene. These mutations have provided insight into lipid metabolism, disease associations, and the basis for drug development to lower LDL-C in disorders linked to hypercholesterolemia. Data from large, randomized trials show that PCSK9 inhibitors lowered the risk of cardiovascular events without apparent adverse sequelae. However, adverse sequelae can occur in FHBL1 and ABL with clinical manifestations, ranging from none to severe, debilitating and life-threatening disorders. Decreased triglyceride transport from the liver can result in fatty liver, cirrhosis, and hepatocellular carcinoma in FHBL and ABL. However, loss-of-function mutations in PCSK-9 and ANGPTL3 do not cause hepatic steatosis. Early diagnosis and treatment are necessary to prevent adverse sequelae from FHBL and ABL. This chapter summarizes recent genetic, metabolic and clinical findings along with diagnostic and management strategies.
Cholesterol is an essential component of animal cell membranes. During the day, 250–500 mg of cholesterol are absorbed continuously from normal food. In a healthy person, maximum cholesterol synthesis ranges between 0.5 and 1 g per day, often occurring at night, between 2:00 and 3:00 a.m. Hypocholesterolemia is a phenomenon that can be observed especially in severe acute conditions. Epidemiological and interventional studies indicate that cholesterol optimal level is restricted to 4.5–5.0 mmol/L; further, the associated normal plasma LDL cholesterol level has been estimated in 2.5–3.0 mmol/L. The accompanying acute inflammatory process produces hypocholesterolemia on a regular basis; therefore, cholesterol can be seen as a “negative reactant” of the acute inflammatory process. Severe depletion of serum cholesterol and LDL cholesterol manifests cortisol deficiency under stress. High mortality rate was observed when the concentration of plasma cholesterol was less than 1.50 mmol/L, or less 40% than their presurgery or pretrauma level, persisting in this manner for more than 6 days.
Hyperlipidemia and dyslipidemia are commonly encountered in clinical practice. Several guidelines and strategies exist for addressing abnormal cholesterol values with the goal of reducing risk of atherosclerotic cardiovascular disease (ASCVD). Beyond primary and secondary measures to reduce risk of ASCVD, clinicians also need to be familiar with genetic lipid disorders and secondary causes of dyslipidemia. Statins continue to remain an essential treatment strategy for ASCVD risk reduction, although many other classes of lipid-lowering pharmacologic agents exist for specific needs. Strategies for reducing cholesterol levels and addressing clinical outcomes are discussed in this chapter.
Cholesterol is the most interesting and the most studied membrane molecule. The knowledge of its fundamental interaction with other molecules can help us to understand the biological functions of cholesterol. This article reviews a conceptual model, the Umbrella model, which has been developed to describe the key interaction between cholesterol and other membrane lipids. The cholesterol molecule has a small polar hydroxyl headgroup and a large nonpolar body (i.e., the steroidal ring structure). The imbalance in size of polar headgroup vs. nonpolar body determines that cholesterol in a lipid bilayer partially relies on the coverage from the headgroups of neighboring lipids to avoid the unfavorable free energy of cholesterol contact with water. This coverage requirement leads to some interesting behaviors; thus, cholesterol prefers lipids with a large headgroup and saturated acyl chains, produces the “condensing effect” and reduces membrane permeability, is capable of inducing formation of membrane domains, has a strong tendency to minimize the size of its own clusters in a bilayer, and competes with other small-headgroup molecules, such as ceramide and diacylglycerol, for large headgroup lipids. A number of important experiments, thermodynamics calculations, and computer simulations that have been used to develop and validate the Umbrella model will be discussed. The Umbrella model can be used as an effective tool to understand and predict the behavior of cholesterol in biomembranes.
The most fundamental function of the plasma membrane (PM) is to enclose the cell and enable the exchange of materials and information between the interior and exterior of the cell. The main structural element of the PM is the lipid bilayer, which determines the bulk membrane properties, provides the environment for integral membrane proteins, and affects their functioning. Membrane proteins control transportation and communication between the inside and outside of the cell. Membrane proteins locate, function, and assemble in membrane domains with specific properties. Cholesterol plays a crucial role in forming such domains. In this review, we discuss the major membrane physical properties induced and controlled by cholesterol in model and intact PMs. They all are analyzed as a function of membrane depth. Finally, we discuss the relationship between these properties and the functions of certain cell types in eukaryotic organisms.
