Cholesterol is the principal sterol of all higher animals,distributed in body tissues,especially the brain and spinal cord,and in animal fats and oils.
Lipids are a broad group of organic compounds which include fats,waxes,sterols,fat-soluble vitamins,monoglycerides,diglycerides,phospholipids,and others. The functions of lipids include storing energy,signaling,and acting as structural components of cell membranes. Lipids have applications in the cosmetic and food industries,and in nanotechnology.
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid molecules in water,as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center,surrounded by a phospholipid outer shell,with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein,called apolipoprotein,is embedded in the outer shell,both stabilising the complex and giving it a functional identity that determines its role.
The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor that recognizes apolipoprotein B100 (ApoB100),which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL),their remnants—i.e. intermediate-density lipoprotein (IDL),and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which is found in chylomicron remnants and IDL. In humans,the LDL receptor protein is encoded by the LDLR gene on chromosome 19. It belongs to the low density lipoprotein receptor gene family. It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.
Scramblase is a protein responsible for the translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane. In humans,phospholipid scramblases (PLSCRs) constitute a family of five homologous proteins that are named as hPLSCR1–hPLSCR5. Scramblases are members of the general family of transmembrane lipid transporters known as flippases. Scramblases are distinct from flippases and floppases. Scramblases,flippases,and floppases are three different types of enzymatic groups of phospholipid transportation enzymes. The inner-leaflet,facing the inside of the cell,contains negatively charged amino-phospholipids and phosphatidylethanolamine. The outer-leaflet,facing the outside environment,contains phosphatidylcholine and sphingomyelin. Scramblase is an enzyme,present in the cell membrane,that can transport (scramble) the negatively charged phospholipids from the inner-leaflet to the outer-leaflet,and vice versa.
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols,SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences,thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.
Foam cells,also called lipid-laden macrophages,are a type of cell that contain cholesterol. These can form a plaque that can lead to atherosclerosis and trigger myocardial infarction and stroke.
The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs,FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol,fatty acid,and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors,however,upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.
The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and intracellular membranes. Some family members are also believed to transport lipophilic molecules from outer cell membrane to certain intracellular receptors such as PPAR. The FABPs are intracellular carriers that “solubilize”the endocannabinoid anandamide (AEA),transporting AEA to the breakdown by FAAH,and compounds that bind to FABPs block AEA breakdown,raising its level. The cannabinoids are also discovered to bind human FABPs that function as intracellular carriers,as THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. Levels of fatty-acid-binding protein have been shown to decline with ageing in the mouse brain,possibly contributing to age-associated decline in synaptic activity.
Phosphatidylethanolamine N-methyltransferase is a transferase enzyme which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. In humans it is encoded by the PEMT gene within the Smith–Magenis syndrome region on chromosome 17.
Stearoyl-CoA desaturase is an endoplasmic reticulum enzyme that catalyzes the rate-limiting step in the formation of monounsaturated fatty acids (MUFAs),specifically oleate and palmitoleate from stearoyl-CoA and palmitoyl-CoA. Oleate and palmitoleate are major components of membrane phospholipids,cholesterol esters and alkyl-diacylglycerol. In humans,the enzyme is present in two isoforms,encoded respectively by the SCD1 and SCD5 genes.
ATP-binding cassette transporter ABCA1,also known as the cholesterol efflux regulatory protein (CERP) is a protein which in humans is encoded by the ABCA1 gene. This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis.
Liver X receptor alpha (LXR-alpha) is a nuclear receptor protein that in humans is encoded by the NR1H3 gene.
Liver X receptor beta (LXR-β) is a member of the nuclear receptor family of transcription factors. LXR-βis encoded by the NR1H2 gene.
ATP-binding cassette sub-family G member 1 is a protein that in humans is encoded by the ABCG1 gene. It is a homolog of the well-known Drosophila gene white.
Adipose differentiation-related protein,also known as perilipin 2,ADRP or adipophilin,is a protein which belongs to the perilipin (PAT) family of cytoplasmic lipid droplet (CLD)–binding proteins. In humans it is encoded by the ADFP gene. This protein surrounds the lipid droplet along with phospholipids and is involved in assisting the storage of neutral lipids within the lipid droplets.
Lipid droplets,also referred to as lipid bodies,oil bodies or adiposomes,are lipid-rich cellular organelles that regulate the storage and hydrolysis of neutral lipids and are found largely in the adipose tissue. They also serve as a reservoir for cholesterol and acyl-glycerols for membrane formation and maintenance. Lipid droplets are found in all eukaryotic organisms and store a large portion of lipids in mammalian adipocytes. Initially,these lipid droplets were considered to merely serve as fat depots,but since the discovery in the 1990s of proteins in the lipid droplet coat that regulate lipid droplet dynamics and lipid metabolism,lipid droplets are seen as highly dynamic organelles that play a very important role in the regulation of intracellular lipid storage and lipid metabolism. The role of lipid droplets outside of lipid and cholesterol storage has recently begun to be elucidated and includes a close association to inflammatory responses through the synthesis and metabolism of eicosanoids and to metabolic disorders such as obesity,cancer,and atherosclerosis. In non-adipocytes,lipid droplets are known to play a role in protection from lipotoxicity by storage of fatty acids in the form of neutral triacylglycerol,which consists of three fatty acids bound to glycerol. Alternatively,fatty acids can be converted to lipid intermediates like diacylglycerol (DAG),ceramides and fatty acyl-CoAs. These lipid intermediates can impair insulin signaling,which is referred to as lipid-induced insulin resistance and lipotoxicity. Lipid droplets also serve as platforms for protein binding and degradation. Finally,lipid droplets are known to be exploited by pathogens such as the hepatitis C virus,the dengue virus and Chlamydia trachomatis among others.
13-Hydroxyoctadecadienoic acid (13-HODE) is the commonly used term for 13(S)-hydroxy-9Z,11E-octadecadienoic acid (13(S)-HODE). The production of 13(S)-HODE is often accompanied by the production of its stereoisomer,13(R)-hydroxy-9Z,11E-octadecadienoic acid (13(R)-HODE). The adjacent figure gives the structure for the (S) stereoisomer of 13-HODE. Two other naturally occurring 13-HODEs that may accompany the production of 13(S)-HODE are its cis-trans (i.e.,9E,11E) isomers viz.,13(S)-hydroxy-9E,11E-octadecadienoic acid (13(S)-EE-HODE) and 13(R)-hydroxy-9E,11E-octadecadienoic acid (13(R)-EE-HODE). Studies credit 13(S)-HODE with a range of clinically relevant bioactivities;recent studies have assigned activities to 13(R)-HODE that differ from those of 13(S)-HODE;and other studies have proposed that one or more of these HODEs mediate physiological and pathological responses,are markers of various human diseases,and/or contribute to the progression of certain diseases in humans. Since,however,many studies on the identification,quantification,and actions of 13(S)-HODE in cells and tissues have employed methods that did not distinguish between these isomers,13-HODE is used here when the actual isomer studied is unclear.
GRAM domain containing 1A also known as Aster-A is a protein that is encoded by the GRAMD1A gene. It contains a transmembrane region,a GRAM domain and a VASt domain that can bind cholesterol. GRAMD1A has four paralogs:GRAMD1B and GRAMD1C and two without VASt domains,GRAMD2A and GRAMD2B. These proteins are mammalian representatives of the yeast lipid transfer proteins anchored at a membrane contact site (LAM) family.
VAD1 analog of StAR-related lipid transfer (VASt) is a steroidogenic acute regulatory protein‐related lipid transfer (StART)-like lipid-binding domain first identified in the vad1 protein in Arabidopsis thaliana. Proteins containing these domains are found in eukaryotes and usually contain another lipid-binding domain,typically the GRAM domain and sometimes the C2 domain in plants and the integral peroxisomal membrane peroxin Pex24p domain in oomycetes.
