lipoprotein and lipid transport

lipoprotein is

particle that consist of protein and lipid, has single monolayer of phospholipid inside lipoprotein theres TAG and cholesteryl esters

protein assocaited with lipoprotein called

apolipoproteins

lipoprotein cargo

TG and CE

lipoprotein membrane has

phosphatidylcholine (PC) and sphinomyelin (SM)

SM in lipoprotein originate from ____ where its generated via de novo pathway of sphingolipid synthesis and into ____ for secretion in circulation

liver, VLDL

apolipoprotein are

protein component of lipoprotein particle, help stabilize structure and key role in metabolism, has 4 componets

APOB48,B100,A

structural protein for HDL, chylomicron, VLDL, HDL, needed for de novo synthesis of lipoproteins

APO C

involved in lipoprotein metabolism by regulation of enzyme

APO E

ligand with high bind affinity to LDL receptor

APO B100

weak ligand for LDL receptor

TAG high to low

chylomicron, VLDL, IDL, LDL

cholesterol content high to low

LDL, IDL, VLDL, chylomicron

lipoprotein classified by

density and size

chylomicrons are

large particle that carry dietary lipids, first type produced in body after TAG, has APO B48 structural protein, made within enterocyte and released in to lymph duct before going to blood stream

VLDL (very low density lipoprotein)

carry endogenous TAG, APO B100 strctural protein

IDL (intermediate density lipoprotein)

carry cholesterol ester and TAG, (VLDL remnant), same APO B100 structural protein

LDL (low density lipoprotein)

carry cholesterol ester from liver to rest of body, APO B100, bad cholesterol

HDL (high density lipoprotein)

carry cholesterol ester from organ back to liver for degradation, good cholesterol, APO A

chylomicron, VLDL, HDL from

de novo synthesized

IDL and LDL derived from

VLDL

APO E has higher affniity to LDLR compared to

APO B100

LDL and LDLR bind trigger

LDL internalization and cholesterol uptake

scavenger receptor for lipoprotein

expressed in phagocyte, ligands are chemically modified LDL, not feedback regulated by intracellular cholesterol

SREBP is

master controller of intracellular cholesterol homeostasis

oxysterol inhibits

SREBP activation

SREBP actiavtion lead to

upregulation of LDLR and HMG-COA reductase, LXR → ABC transporter for cholesterol efflux

intracellular cholesterol homeostasis maintained by regulate

LDLR, HMG-COA reductase, ABC transporters

when cholesterol high

SREBP decrease → LDLR decrease → decrease cholesterol intake

LXR increase → ABCA1/ABCG1 increase → increase cholesterol efflux

when cholesterol low

SREBP increase→ LDLR increase→ increase cholesterol intake

LXR decrease→ ABCA1/ABCG1 decrease→ decrease cholesterol efflux

enzymes and protein involved in lipid transport

lipase, acyl transferase, cholesterol/cholesterol ester transfer protein

lipase

hydrolyze TAG from lipoprotein particles to glycerol and fatty acid

LPL, HTGL

acyl transferase

esterifies cholesterol

-LCAT, ACAT

cholesterol/cholesterol ester transfer protein

facilitates the transfer of cholesterol or exchange of cholesteryl esters for TAG

ABCA1 and ABCG1, CETP

LPL

bound to heparan sulfate proteoglycan on surface of vascular endothelial cell, digest TAG in chylomicron and VLDL and release fatty acid and glycerol into cell

HTGL

associated with plasma membrane in liver, act on particle that partially digested by LPL and faciliatae conversion of IDL to LDL

location and substrate of LPL

peripheral tisssue, chylomicron/VLDL

location and substrate of HTGL

hepatocytes, remnants

ACAT

excess cholesterol stored as CEs in cytosolic lipid droplet, adds FFA to cholesterol to form Ces, esterify cholesterol inside cells

LCAT

reverse HDL, synthesized in liver,

ABCA1 tranfers

free cholesterol to lipid poor HDL

ABCG1 transfer

free cholestorl to mature HDL

CETP

mediates exchange of CE and TG between CE rich high density lipoprotein and VLDL

fuel transport fed state chylomicrons

transport TAG from intestine to periphery, APOB48 for chylomicron biosynthesis and APOE for ligand for LDLR, short half life

fuel transport fasting state VLDL

transports liver-produced TGs (fuel) to peripheral tissues and eventually becomes LDL, needs APOB100 for synthesis and APOE as ligand for LDLR, short half life

overflow pathway of lipid metabolism

VLDL → LPL removes TG → IDL (VLDL remnant) → HTGL removes more TG; ApoE dissociates → LDL → Binds LDL receptors (LDLR) → Peripheral cells / Liver → Cholesterol delivery and LDL clearance, long half life

reverse cholesterol transport

• Direct: HDL3 → SR-BI → CE enters liver.

• Indirect: CETP transfers CE to VLDL/IDL → liver

• longest half life bc doesnt have APOB100 or ABOE, HDL cant be removed by LDLR binding

familial combined hyperlipidemia

overproduction APOB100, increased VLDL (fuel transport), increased LDL (overflow pathway)

familial chylomicronemia syndrome/lipoprotein lipase deficiency

rare dyslipidemia, affect fuel transport pathway, deficiency of LPL, risk of pancreatitis

familial dysbetalipoproteinemia

affect fuel transport pathway, mutation in APOE, remnant accumulates, increase cholesterol and TAG in plasma

familial hypercholesterolemia

monogenic disorder, mutatuion for APOB/E receptor, affect overflow pathway, uptake and LDL impareid or inhibited, APOB100 overproduced/APOE deficient/LDLR deficient

APOB100 overproduced/APOE deficient/LDLR deficient associated with

hypercholesterolemia

atherosclerotic plaque

MMPs degrade the collagen cap → plaque ruptures → thrombus forms → blood flow becomes obstructed

atherogenesis earliest event _______________ followed by _____________

endothelial dysfunction, inflammation/monocyte transmigration/lipid deposition (foam cell)/smooth muscle cell migration and proliferation

atherogenesis late events

plaque rupture leading to thrombosis

in atherogenesis expression of SR not feedback regulated by intracellular cholesterol thus

macrophages overload with cholesterol cause accumulation of lipid droplet and transformation into foam cells

treatments of dyslipidemias

lifestyle modification, omega 3 fatty acids, antioxidants, PPARa agonists, HMG-COA reductase inhibitor, cholesterol absorption inhibitor, PCSK9 inhibitor

life style modification

diet, exercise, smoke/drink cessation

omega 3 fatty acids

lower plasma TAG

antioxidants

vitamin E/C, B-carotene

PPARa agonists

activate LPL, decrease TAG, increase HDL-C

HMG-COA reductase inhibitor

statin - decrease intracellular cholesterol synthesis

cholesterol absorption inhibitor

ezetimibe - inhibit intestinal cholesterol transporter NPC1L1, lower total cholesterol by 20%

PCSK9 inhibitor

alirocumab - increase LDLR expression and lower plasma cholesterol

PCSK9 production

hepatocytes is predominant site

PCSK9 shows

change and locks LDLR in open conformation preventing its recycling, LDLR then routed to lysosomes for degradation

Statins: Increase LDL Receptor Production

Increased LDL uptake by the liver → decreased plasma LDL cholesterol

PCSK9 Inhibitors: Prevent LDL Receptor Degradation

More available LDL receptors → increased LDL clearance → decreased plasma LDL cholesterol