Cholesterol and lipoproteins

Explain cholesterol structure in regards to plasma

esterified form with fatty acid attached at carbon 3

Explain cholesterol structure

4-ringed steroid nucleus, hydroxyl group attached to first ring, and short hydrocarbon side chain at the other end

what is cholesterol

structural component of all cell membranes, modulating their fluidity. and precursor of bile acids/steroid hormones/vit D

What is the role of NPC1L1 in regards to cholesterol

mediates uptake of cholesterol from intestine into enterocytes and hepatic reuptake of cholesterol from bile into hepatocytes

What is the role of ABCG5/8 in regards to cholesterol

regulate cholesterol levels via pumping cholesterol out of liver cells into bile and out of intestinal cells back into gut lumen

What inhibits NPC1L1 resulting in reduce absorption of dietary cholesterol

Ezetimibe

What is Sitosterolemia (aka phytosterolemia)

autosomal recessive disorder associated with defects in ABCG5/8 transporter

Where are cholesterol esters found

only at low levels in most cells

How is cholesterol and its esters transported

as a component of lipoprotein particle or solubilized by phospholipids and bile salts in bile

What tissues/organs synthesize the most cholesterol

liver, intestine, adrenal cortex, and reproductive tissue

Explain cholesterol biosynthesis

all carbon atoms in cholesterol are provided via acetyl CoA

NADPH provide reducing equivalents

pathway endergonic, driven by hydrolysis of higher energy thioester bond of acetyl CoA and terminal phosphate bond of ATP

requires enzymes in cytosol, sER membrane and peroxisome

responsive to changes in cholesterol concentration and regulatory mechanisms exist to balance rate of cholesterol synthesis against rate of cholesterol excretion

What can an imbalance of cholesterol regulation lead to

elevation in circulating levels of plasma cholesterol with potential for vascular disease

What is 3-Hydroxy-3-methylglutaryl CoA synthesis

two acetyl CoA molecules condense = acetoacetyl CoA

third molecule of acetyl CoA is added via HMG CoA synthase = HMG CoA six carbon compound

liver parenchymal cells contain two isoenzymes of synthase

cytosolic enzyme participate in cholesterol synthesis

mitochondrial enzyme function in pathway for ketone body synthesis

What is mevalonate synthesis

HMG CoA reduce to mevalonate via HMG CoA reductase (rate limiting and key regulated step in cholesterol synthesis)

uses 2 NADPH molecules as reducing agent and release CoA making reaction irreversible

HMG CoA reductase is an integral membrane protein of sER with its catalytic domain projecting into cytosol

Where in the cell does mevalonate synthesis occur

cytosol

how many molecules of NADPH is used during mevalonate synthesis

2

What type of synthesis is shown

cholesterol synthesis from mevalonate

What does the image show

Cholesterol synthesis regulation

what are the 3 hormonal regulation components in cholesterol synthesis regulation

insulin

glucagon

epinephrine

what are the 2 sterol-independent phosphorylation/dephosphorylation components in cholesterol synthesis regulation

AMPK

phosphoprotein phosphatase

What is the sterol-dependent regulation of gene expression and sterol-accelerated enzyme degradation involved in cholesterol synthesis regulation

Sterol-dependent regulation of gene expression: sterol regulatory element binding protein-2 (SREBP-2)

sterol accelerated enzyme degradation: insulin-induced gene proteins (INSIGs)

What are statins

class of prescription drugs used to lower high cholesterol by blocking an enzyme in the liver that produces cholesterol

what is the benefit of statins in regards to LDL cholesterol

decreases amount of LDL cholesterol in blood and increases the liver’s ability to remove it from bloodstream

slow the buildup of plaque in arteries, reducing risk of heart attack/stroke

What are structural analogs of HMG CoA

statins

What are reversible, competitive inhibitors of HMG CoA reductase

statin drugs like atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin

How is cholesterol degradation managed

via processes like reverse cholesterol transport (RCT) to the liver or releases of cholesterol within desquamating cells

How is cholesterol degraded within the body through RCT

intact steroid nucleus of cholesterol is eliminated from body via conversion to bile acids/salts, small percentage excreted in feces, and by secretion of free cholesterol into bile, which transports it to intestine for elimination

what are the primary compounds made when bacteria in the intestine modify some cholesterol before excretion, 

reduced derivatives of cholesterol; coprostanol and cholestanol (isomers of each other)

What are the most important organic components of bile

PC, or lecithin and conjugated bile salts

Explain cholesterol transport

cholesterol transported via lipoproteins, both to tissues for use (via particles like LDL) and away from tissues to the liver via RCT that primarily involves HDL

inside cells cholesterol trafficked between organelles via vesicular transport and non-vesicular mechanisms that can involve sterol transfer proteins and membrane contact sites

What is Enterohepatic circulation

continuous cycle of bile salt secretion into the bile, pass through duodenum (some are deconjugated then dehydroxylated → secondary bile salts), uptake in ileum and subsequent return to the liver (mixture of primary/secondary forms)

What is the function of bile acid sequestrants (like cholestyramine) and its importance

bind to bile salts in gut, preventing reabsorption→ promoting excretion which relives inhibition of bile acid synthesis in liver therefore cholesterol is used in this pathway

importance: useful in treatment of hypercholesterolemia

What can lead to cholesterol gallstone disease or cholelithiasis

more cholesterol present than can be solubilized by the bile salts and PC present, cholesterol precipitate in gallbladder

what causes disorder of gallstone disease

decrease of bile acids in bile or also result from increased secretion of cholesterol into bile, seen with use of fibrates to reduce cholesterol and TAG in blood

what are the lipoprotein classes

1. Chylomicrons

2. chylomicron remnants

3. very low density lipoproteins= VLDL

4. intermediate-density lipoproteins (IDL); which are VLDL remnants

5. low density lipoproteins (LDL)

6. high-density lipoproteins (HDL)

7. lipoprotein (Lp[a])

What is the composition of plasma lipoproteins

neutral lipid core (made of TAG + cholesteryl esters)

shell of amphipathic apolipoproteins, phospholipids and free cholesterol

what are apolipoproteins and their importance

proteins that bind to lipids to form lipoproteins

importance: provide recognition sites for cell-surface receptors or serve as activators/ coenzymes for enzymes involved in lipoprotein metabolism

What type of apolipoprotein functions as essential structural components of particles and cannot be removed (particles cannot be produced without them)

non-exchangeable apolipoproteins

What are some important non-exchangeable apolipoproteins

apoB-48 and apoB-100

What type of apolipoproteins are transferred freely between lipoproteins

exchangeable apolipoproteins

what are some important exchangeable apolipoproteins

apoAs

apoCs

apoEs

What is required for the assembly of apolipoprotein and lipid into chylomicrons

microsomal triglyceride transfer protein (MTP) → loads apo B-48 with lipid in ER

In Chylomicron assembly where are the particles moved from and to, and how are they packaged and transfered

particles move from ER to Golgi

at Golgi particles are packaged in secretory vesicles which then fuse with plasma membrane releasing chylomicron particles which enter lymphatic system and ultimately blood

What is the particle released by intestinal mucosal cell and why

nascent chylomicron because its functionally incomplete

How is TAG degraded by LPL

LPL is activated by apo C-II on circulating chylomicrons, which hydrolyzes the TAG to fatty acid (stored in adipose or used as energy in muscles) and glycerol (taken up by liver, converted to dihydroxyacetone phosphate for lipid synthesis or gluconeogenesis)

What is a deficiency of LPL and its effects

type I hyperlipoproteinemia/familial chylomicronemia

dramatic accumulation of chylomicron-TAG in plasma even in fasted state

Type IB hyperlipoproteinemia→ results from deficiency in apo C-II

what plays a role in TAG degradation

hepatic lipase on surface of endothelial cells of the liver

Where are VLDLs produced, their composition and their function

produced in liver

composed predominantly of endogenous TAGs

function: carry this lipid from liver (site of synthesis) to peripheral tissues

How is IDLs and LDLs converted

VLDL converted in plasma to LDL

IDLs can be taken up by liver cells through receptor mediated endocytosis that uses apo E as ligand

What are the 3 isoforms of Apo E and their effects 

Least common: E-2, poorly binds to receptors and those who are homozygotic for it are deficient in the clearance of IDL and chylomicron remnants. Have familial type III hyperlipoproteinemia

Most common: E-3

E-4: confers increased susceptibility to an earlier age of onset to late-onset form of Alzheimer disease

How do statins reduce cholesterol synthesis in LDL receptor mediated endocytosis

via inhibiting HMG-CoA reductase

Resulting in increase production of LDLR

how does statins work in reducing atherosclerotic cardiovascular diseases

two main biochemical mechanisms: inhibiting cholesterol synthesis and triggering pleiotropic (cholesterol independent) anti-inflammatory effects via blocking key enzyme in liver, statins decrease amount of “bad” cholesterol (LDL-C)

what is dyslipidemia

abnormal levels of cholesterol-carrying lipoproteins in blood caused by disruptions in body’s complex biochemical pathways for lipid metabolism

what are the dyslipidemia mechanisms and what they lead to

lead to overproduction or defective clearance of cholesterol and other lipids → imbalance of LDL and HDL cholesterol

mechanisms: involve in several stages of lipoprotein metabolism like; abnormal VLDL production, impaired processing of VLDL into LDL, defective LDL clearance, dysfunctional HDL, and genetic vs secondary causes

how does dyslipidemia mechanisms relate with ASCVD pathobiology and therapy

Dyslipidemia= central driver of atherosclerotic cardiovascular disease (ASCVD) through its role in formation and progression of arterial plaque. therapies target lipid abnormalities of ASCVD prevention and treatment

what is the structure of bile acids/salts and what are the most abundant bile acids in human bile

structure: 24 carbons with 2-3 hydroxyl groups and side chain that terminates in a carboxyl group

most abundant: cholic acid and chenodeoxycholic acid

What is the function of apoAs and their primary source

primary sources: intestine and liver

structural for HDL, activation of LCAT and HI, promotes LPL mediated TG-lipolysis

What is the function of apoCs and their primary source

primary source: Liver

activation of LCAT, cofactor for LPL, inhibits LPL and uptake of lipoproteins

What is the function of apoEs and its primary source

ligand for binding to LDLR

primary source: liver

Describe an overview of Chylomicron metabolism

assembled in intestinal mucosal cells and carry dietary (exogenous) TAGs, cholesterol, fat-soluble vitamins, and cholesteryl esters to peripheral tissues

What is the 5 overall steps in chylomicron metabolism

1. intestinal mucosal cells secrete nascent TAG-rich chylomicrons

2. ApoC-II and apo E are transferred from HDL to nascent chylomicron

3. Extracellular lipoprotein lipase, activated by apoC-II, degrades TAG in chylomicrons

4. ApoC-II is returned to HDL

5. CE-rich chylomicron remnants bind through apo E to specific receptors on the liver and are endocytosed

What is the process shown in the image

Chylomicron metabolism

What is Apo48

form of apolipoprotein B

synthesized in intestine, specific to chylomicrons; dietary fat absorption

What is ApoB100

form of apolipoprotein B

produced by liver, found in VLDL, IDL, and LDL particles

transport cholesterol and triglycerides throughout the body

What apolipoprotein B is the result of post-transcriptional RNA editing; C→U, creating a stop codon in apoB mRNA

ApoB48

what reduces LDLR recycling

proprotein convertase subtilisin/kexin type 9 (PCSK9)

What is autosomal dominant familial hypercholesterolemia 3 associated with

gain of function in PCSK9, which promotes lysosomal degradation of LDLR

How is synthesis of new LDLR protein reduced

via decreasing expression of LDLR gene, limiting further entry of LDL-C

What is the result if cholesterol is not required immediately for structural or synthetic purpose

its esterified by acyl CoA: cholesterol acyltransferase (ACAT) which transfers a fatty acid from fatty acyl CoA to cholesterol→ producing cholesteryl ester that can be stored in the cell

How is activity of ACAT enhanced when cholesterol is not required immediately for structural/synthetic purpose

enhanced in presence of increased intracellular cholesterol

What is the importance of scavenger receptors (SRs) specifically SR-A and what other cellular component possess high levels of it

Macrophage possess high levels of SRs

SR-A can bind a broad range of ligands and mediate endocytosis of chemically modified LDL, especially oxidized LDL (oxLDL)

How is SRA different from LDLR

SRA is not downregulated in response to increased intracellular cholesterol

cholesteryl esters accumulate in macrophages causing their transformation into “foam” cells that participate in formation of atherosclerotic plaque

Where are high density lipoproteins (HDLs) formed and how are they formed

formed in blood by addition of lipid to apoA-1 (made/secreted by liver and intestine as lipid poor protein)

what type of particle serves as circulating reservoir of apo C-II and apo E

HDL particles

In HDL metabolism how is free cholesterol uptake

nascent HDLs containing primarily phospholipid and apo A/C/E, take up free cholesterol from non-hepatic peripheral tissues and return it to liver as cholesteryl esters

ABCA1 & ABCG1 mediate free cholesterol uptake from peripheral cells to lipid poor apoAI and HDL particles

In HDL metabolism how does cholesterol esterification happen

cholesterol taken up by HDL→ immediately esterified by plasma enzyme lecithin: cholesterol acyltransferase (LCAT) which transfers fatty acid from carbon 2 of PC to cholesterol

esterification maintains cholesterol concentration gradient→ allows continued efflux of cholesterol to HDL

discoidal nascent HDL accumulates cholesteryl esters it becomes spherical cholesteryl ester poor HDL3→ cholesteryl ester rich HDL2 particle

what is the function of CETP in HDL metabolism cholesterol esterification

transfers some cholesteryl esters from HDL to VLDL in exchange for TAG

why is reverse cholesterol transport important

key component of cholesterol homeostasis and essence of HDL metabolism so cholesterol from peripheral cells to apoAI/HDL and from HDL to liver for bile acid synthesis/disposal