Cholesterol, Lipoproteins, and Cardiovascular Disease

Comprehensive practice flashcards covering cholesterol structure, biosynthesis, transcriptional regulation, lipoprotein classes and metabolism, atherosclerosis pathogenesis, and therapeutic modalities based on lecture notes.

Total Cholesterol Classification

Clinical risk categories based on plasma cholesterol levels: Desirable ($< 200\,mg/dL$), Borderline High ($200 - 239\,mg/dL$), and High ($\ge 240\,mg/dL$).

Cholesterol (Chemical Structure)

A $27$-carbon ($C27$) steroid lipid comprising four fused hydrocarbon rings (three $6$-carbon rings and one $5$-carbon ring), a single polar hydroxyl ($-OH$) group at $C3$, a double bond between $C5$ and $C6$, and an $8$-carbon branched hydrocarbon tail attached to $C17$.

Plasma Membrane Lipid Composition

The relative lipid composition of human cell membranes, typically consisting of approximately $75\%$ phospholipids, $20\%$ cholesterol, and $5\%$ glycolipids.

HMG-CoA Reductase

An integral endoplasmic reticulum membrane enzyme that catalyzes the committed, irreversible, and rate-controlling step of cholesterol synthesis: the reduction of HMG-CoA to mevalonate using $2\,\text{NADPH}$ and releasing free $CoA$.

Cholesterol Biosynthesis Pathway

The sequential enzymatic cascade converting acetyl CoA into cholesterol via intermediate stages: Acetyl CoA $\rightarrow$ Acetoacetyl CoA $\rightarrow$ HMG-CoA $\rightarrow$ Mevalonate ($C6$) $\rightarrow$ Isopentenyl Pyrophosphate ($C5$) $\rightarrow$ Geranyl Pyrophosphate ($C10$) $\rightarrow$ Farnesyl Pyrophosphate ($C15$) $\rightarrow$ Squalene ($C30$) $\rightarrow$ Lanosterol $\rightarrow$ Cholesterol ($C27$).

Competitive Inhibition of HMG-CoA Reductase by Statins

The pharmacologic mechanism in which statins (such as simvastatin, atorvastatin, and pravastatin) reversibly inhibit HMG-CoA reductase because their polar head groups closely mimic the 3-hydroxy-3-methylglutaryl moiety of the endogenous substrate HMG-CoA.

SREBP (Sterol Regulatory Element-Binding Protein)

A membrane-bound transcription factor in the endoplasmic reticulum whose precursor complexes with SCAP; upon cholesterol depletion, it travels to the Golgi, undergoes sequential cleavages, and releases a soluble basic helix-loop-helix DNA-binding domain that enters the nucleus to bind sterol regulatory elements (SRE) and stimulate transcription.

SCAP (SREBP Cleavage-Activating Protein)

An endoplasmic reticulum sterol-sensing protein that forms a stable complex with SREBP; it escorts SREBP to the Golgi apparatus when cellular cholesterol is low, but binds to Insig and remains retained in the ER membrane when cholesterol is elevated.

Insig

An endoplasmic reticulum membrane protein that binds SCAP when membrane cholesterol concentrations are high, preventing the translocation of the SREBP-SCAP complex to the Golgi and shutting off cholesterol synthesis gene expression.

AMPK Regulation of HMG-CoA Reductase

A covalent post-translational regulatory mechanism wherein AMP-activated protein kinase (AMPK) inactivates HMG-CoA reductase by phosphorylation, whereas phosphoprotein phosphatase (PPP) restores enzymatic activity via dephosphorylation.

ACAT (Acyl CoA:cholesterol acyltransferase)

An intracellular enzyme located in the endoplasmic reticulum that catalyzes the esterification of free membrane cholesterol with a fatty acyl-CoA into a neutral cholesteryl ester for storage in lipid droplets or transport within lipoproteins.

Primary Bile Acids

Twenty-four-carbon ($C24$) amphipathic steroids synthesized from cholesterol in the liver, primarily cholic acid (a triol) and chenodeoxycholic acid (a diol), containing polar hydroxyl groups oriented to facilitate lipid digestion.

Bile Salts

Detergent molecules synthesized by hepatocytes via the amide conjugation of primary bile acids with either glycine or taurine in an approximate $3:1$ ratio (forming glycocholic acid and taurochenodeoxycholic acid), substantially enhancing their water solubility and detergent power.

Enterohepatic Circulation

The physiological circuit whereby $15 - 30\,g/\text{day}$ of bile salts are secreted through the bile duct into the intestine, $\ge 97\%$ are actively reabsorbed in the terminal ileum and returned to the liver via the portal vein, and only $\le 0.5\,g/\text{day}$ ($\le 3\%$) is eliminated in feces.

Cholestyramine

An oral bile acid sequestrant resin that binds bile salts in the intestinal lumen to prevent their reabsorption, interrupting enterohepatic circulation and compelling hepatocytes to consume cholesterol to replenish the bile salt pool, thereby upregulating LDL receptors.

Lipoprotein Architecture (Core vs. Shell)

The spherical organization of plasma lipid transport particles comprising a hydrophobic nonpolar core containing cholesteryl esters (CE) and triacylglycerols (TAG), enveloped by an amphipathic shell of phospholipids (PL), free cholesterol (C), and apolipoproteins (P).

Proposed Structure of Intestinal Mixed Micelle

A discoidal bilayer aggregate having a protective perimeter of amphipathic bile salts enclosing interior hydrophobic digestive lipid products, including free fatty acids, monoacylglycerols, phospholipids, and cholesterol, aiding diffusion across the unstirred water layer.

Chylomicrons

The largest ($750 - 12,000\,\text{Å}$) and least dense ($< 0.95\,g\,cm^{-3}$) plasma lipoproteins, synthesized by enterocytes to carry dietary (exogenous) triacylglycerols ($\approx 86\%$) and displaying Apo B-48, Apo C-II, and Apo E.

Apolipoprotein B-48 (Apo B-48)

A structural apolipoprotein synthesized specifically by intestinal mucosal cells that represents the $N$-terminal $48\%$ of full-length Apo B, essential for the packaging and secretion of dietary chylomicrons.

Apolipoprotein C-II (Apo C-II)

An apolipoprotein transferred from HDL to nascent chylomicrons and VLDL that acts as an obligatory cofactor to activate lipoprotein lipase (LPL) on capillary endothelial surfaces, triggering intravascular triacylglycerol hydrolysis.

Apolipoprotein E (Apo E)

An exchangeable surface apoprotein that serves as the high-affinity ligand recognized by the hepatic remnant receptor (LRP) and LDL receptor to clear chylomicron remnants and IDL from systemic circulation.

VLDL (Very Low Density Lipoprotein)

A triacylglycerol-rich ($\approx 52\%$) plasma lipoprotein ($300 - 800\,\text{Å}$, density $0.95 - 1.006\,g\,cm^{-3}$) assembled in the liver to transport endogenous lipids to extrahepatic tissues, presenting Apo B-100, Apo C-II, and Apo E.

IDL (Intermediate Density Lipoprotein)

A remnant lipoprotein ($150 - 350\,\text{Å}$, density $1.006 - 1.019\,g\,cm^{-3}$) enriched in cholesteryl esters formed when lipoprotein lipase removes TAG from VLDL; roughly $50\%$ is cleared by hepatic receptors via Apo E and Apo B-100, while $50\%$ is converted into LDL.

LDL (Low Density Lipoprotein)

A cholesteryl ester-rich plasma lipoprotein ($180 - 250\,\text{Å}$, density $1.019 - 1.063\,g\,cm^{-3}$) that contains a single molecule of Apo B-100 and functions to deliver cholesterol to peripheral tissues and the liver via receptor-mediated endocytosis.

The LDL Receptor Pathway

The cellular uptake system in which LDL binds clathrin-coated pit receptors, is internalized, and is routed to lysosomes where cholesteryl esters are hydrolyzed, freeing cholesterol to (1) suppress HMG-CoA reductase, (2) stimulate ACAT esterification, and (3) downregulate cell surface LDL receptors.

Familial Hypercholesterolemia (FH)

An autosomal dominant disorder exhibiting a gene dosage effect (heterozygotes $1:500$, homozygotes $1:1,000,000$) caused primarily by loss-of-function mutations in the LDL receptor gene, producing severe hypercholesterolemia, tendon and cutaneous xanthomas, atheromas, and early coronary artery disease.

Cutaneous Xanthomas

Nodular or planar yellowish lipid deposits embedded in subcutaneous tissues (hands, feet, elbows, knees) composed of cholesterol-laden macrophage foam cells, characteristically observed in severe homozygous familial hypercholesterolemia.

HDL Discs (Nascent HDL)

Newly secreted, discoidal bilayer complexes of phospholipids, unesterified free cholesterol, and apolipoproteins (predominantly Apo A-I) produced by the liver and intestine or liberated during chylomicron lipolysis.

LCAT (Lecithin:Cholesterol Acyltransferase)

A plasma enzyme activated by Apo A-I that transfers a fatty acyl group from phosphatidylcholine (lecithin) to free cholesterol, generating cholesteryl esters that partition into the hydrophobic core and convert nascent discoidal HDL into mature spherical particles ($\text{HDL}_3 \rightarrow \text{HDL}_2$).

Maturation of HDL

The progressive structural transition of nascent discoidal pre-$\beta$-HDL into small spherical $\text{HDL}_3$ and subsequently larger spherical $\text{HDL}_2$ driven by ongoing LCAT-catalyzed esterification of acquired unesterified peripheral cholesterol.

ABCA1 Transporter

An ATP-dependent membrane efflux pump that mediates the cellular export of excess free cholesterol and phospholipids to lipid-poor Apo A-I, initiating nascent pre-$\beta$-HDL formation.

CETP (Cholesteryl Ester Transfer Protein)

A plasma lipid transfer glycoprotein that facilitates the bidirectional exchange of hydrophobic core lipids, transferring cholesteryl esters from HDL to VLDL, IDL, and LDL in return for triacylglycerols and phospholipids.

SR-B1 (Scavenger Receptor Class B Type 1)

A cell surface receptor on hepatocytes and steroidogenic cells that binds mature HDL particles and selectively extracts cholesteryl esters into the cytoplasm without internalizing or degrading the carrying lipoprotein particle.

Foam Cells

Enlarged macrophages within the subendothelial arterial intima that have massively accumulated oxidized low-density lipoprotein (oxLDL) particles through scavenger receptors, coalescing into early fatty streaks.

Fibro-Fatty Atheroma

An advanced atherosclerotic lesion in the arterial wall consisting of an inner necrotic core of extracellular lipid debris and foam cells shielded by an overlying collagenous fibrous cap synthesized by migrated smooth muscle cells.

Ezetimibe (Zetia)

A cholesterol absorption inhibitor that selectively targets the NPC1L1 transporter on jejunal enterocyte brush borders, preventing intestinal absorption of dietary and biliary cholesterol without blocking triacylglycerol absorption.

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9)

A secreted hepatic protease that binds directly to the epidermal growth factor-like repeat A domain of the cell-surface LDL receptor, targeting the internalized receptor complex to lysosomal destruction and preventing its recycling back to the plasma membrane.

Evolocumab (Repatha)

A fully human monoclonal antibody directed against PCSK9 that prevents PCSK9 from binding to the LDL receptor, preserving LDLR recycling to cell surfaces and reducing circulating plasma LDL-C by up to $61\%$ in high-risk patients.

Inclisiran (Leqvio)

A subcutaneously administered small interfering RNA (siRNA) therapeutic directed against hepatic PCSK9 mRNA, dosed twice yearly after two initial loading doses to sustain a $\approx 50\%$ reduction in plasma LDL-C.

Enlicitide (Lipfendra)

An FDA-approved oral daily tablet ($20\,mg$) that functions as a small molecule inhibitor blocking the physical interaction between PCSK9 and the LDL receptor.

Mipomersen

An antisense oligonucleotide RNA therapeutic designed to bind Apo B-100 mRNA in the liver to block Apo B-100 translation, thereby reducing VLDL and LDL assembly in homozygous familial hypercholesterolemia (discontinued in 2018).

Bempedoic Acid (ETC-1002)

An oral lipid-lowering prodrug converted specifically in hepatocytes by ACSVL1 into active ETC-1002-CoA, which inhibits ATP Citrate Lyase (ACL) upstream of HMG-CoA reductase; its absence in skeletal muscle prevents statin-like myotoxicity.

Evinacumab (ANGPTL3 Inhibition Pathway)

A human monoclonal antibody that blocks angiopoietin-like 3 (ANGPTL3), relieving the inhibition of lipoprotein lipase (LPL) and endothelial lipase (EL) to accelerate lipolysis and promote LDLR-independent uptake of VLDL remnants in homozygous familial hypercholesterolemia.