Lipoprotein and Cholesterol Metabolism

At the physiological level, lipids and lipoproteins are required for ____, _____, ______ and ______

Cell nutrition, growth, membrane structure, energy balance

At the pathological level, lipids and lipoproteins are involved in ______

Mechanism for atherosclerosis and vascular degeneration

At the clinical level, lipids and lipoproteins are important risk factors for ________, ______, _____, and _____

CVD, coronary heart disease, stroke (occlusive), acute pancreatitis

Clinical manifestations of atherosclerosis in CVD: Coronary heart disease

• Stable angina

• Myocardial infarction

• Sudden death

• Unstable angina/NSTEMI

Clinical manifestations of atherosclerosis in CVD: Cerebrovascular disease

• Stroke

• Transient ischemic attacks

Clinical manifestations of atherosclerosis in CVD: Peripheral arterial disease

• Intermittent claudication

• Amputation

Modifiable CVD risk factors

• Smoking

• Hypertension

• Diabetes

• Obesity

• Diet

• Thrombogenic factors

• Sedentary lifestyle

• Dyslipidemia

  • Raised LDL, low LDL, raised TG

Non-modifiable CVD risk factors

• Genetics

• Age

• Gender

Lipids transported in the form of ______ ()

Lipoproteins (spherical microemulsion particles)

Contents of lipoproteins

• Phospholipid

• Cholesterol

• Triglyceride

• Cholesteryl ester

• Apolipoprotein

_____ phospholipids, ______ cholesteryl esters

Amphiphilic, hydrophobic

Lipoproteins are assembled with the help of ____ (ie. ___)

Proteins (apolipoprotein B)

_______ interacts with the aqueous environment (plasma), while _____ interact with the lipophilic component

Lipovitellin-like B-barrel; a helical sheets, amphipathic B sheets

Each LDL has one molecule of _____, a better marker for ____

ApoB, CVD

_____ is the most common lipoprotein in humans

LDL

Lowest to highest density lipoprotein

1. Chylomicron

2. VLDL

3. LDL

4. HDL

Highest to lowest diameter lipoprotein

1. Chylomicron

2. VLDL

3. LDL

4. HDL

Chylomicrons are formed by the ____ after a meal

intestine

_____ is more atherogenic

LDL

_____ is the best lipoprotein but unknown role

HDL

Lipoproteins separated by ____, _____ or ______ by ______

Electrophoresis (outdated), density (fractionation), size, electron microscopy

Chylomicrons are made in the ____ from ___ and mainly contain ____ and ____

small intestine, diet, TGs, apoprotein B48

VLDL is made in the ____ and contains _____

liver, ApoB100

______ converts VLDL → _____ → ____

Lipoprotein lipase (LPL), IDL, LDL

HDL picks up ______ () and transports them to the ____ for breakdown

cholesterol (esters), liver

The liver is the main source of ______, providing _____, ____, and ____ for other cells

lipoprotien packaging, fatty acyl chains, TGs, cholesterol

Exogenous lipoprotein metabolism (6)

• Dietary lipids

• Chylomicrons produced in small intestine (contain ApoC/E/B)

• Drained to lymphatics

• Travel capillaries as LDL

• Transport into muscle and adipose as FFAs + albumin

• Chylomicron remnant binds LDLR in liver and rapidly degraded

FFA in muscle and adipose can be ______ or ______; fatty muscle = _____

hydrolyzed for energy, reassembled into triglycerides, insulin resistance

Endogenous lipoprotein metabolism

• Liver synthesizes VLDL

• Travels capillaries and enters muscle/adipose bound to albumin

• Becomes IDL

• Enters the liver or converted into LDL

• LDL enters liver or enters peripheral tissues

VLDL has its own _____ therefore can sometimes be picked up by tissues directly

receptor

LDL has a longer ____, and is main source of ___ for other tissues and for endocrine glands to _____

half-life, cholesterol, synthesize hormones

_____ isn’t present in HDL, instead it has ____

ApoB, ApoA1

Humans have evolved to absorb _____ of fat, however only half of ______ is absorbed due to ______

100%, consumed cholesterol, ABCA1, ABCG5/8

____ cholesterol synthesized de novo in the _____ and ____

60-80%, liver, intestine

______ cholesterol comes from ____, regulating ________

20-40%, diet, endogenous biosynthesis

________ (300mg/day) + _________ (900mg/day) = ______ (1200mg/day)

Dietary cholesterol, synthesized cholesterol, fecal sterols

_____ is the RDS of cholesterol synthesis

HMG-CoA reductase (conversion of HMG-CoA to mevalonic acid)

____ inhibits HMG-CoA reductase to reduce ______

Statins, cholesterol

_______ promotes conversion of _____ into cholesterol

SREBP activation

Nuclear receptors ___ and ___ mediate transcription of ______ when cholesterol is present

RXR, LXR, Cyp7a

Nuclear receptors _____ and ____ promote transcription of _____ and ____ to convert cholesterol into ____

RXR, FXR, I-BABP, PLTP, bile acids

Cholesterol forms ______ as a byproduct through transcription of ____, _____, and ____ by nuclear receptors ____ and ____

Oxysterols, Cyp7a, ABCA1, ABCG1, RXR, LXR

______ promote SREBP activation

Oxysterols

Cholesterols also form _____

steroid hormones

_______ is formed from the condensation of acetyl-CoA and acetoacetyl-CoA, catalyzed by ______

HMG-CoA, HMG-CoA synthase

_______ catalyzes the production of _____ from HMG-CoA

HMG-CoA reductase, mevalonate

Cholesterol uptake and metabolism in fibroblasts

1. LDL binding

2. Endocytosis

3. Lysosomal hydrolysis

4. Enters golgi

5. Reacts with HMG-CoA reductase

6. Exits via ACAT as cholesteryl oleate

Pool of sterols in the cell also alters ____. Increased _____ = ______ cholesterol

LDLR, decreased

Children born with high LDL at birth have defect in ______. Ideal levels are ______

LDL receptor, <5mmol/L

The _______ interacts with the LDL receptor ________

ApoB C-terminal, N-terminal

Mutations in LDL receptor cause __________, a common _______ genetic disease

Familial hypercholesterolemia, autosomal dominant

______ regulates cholesterol metabolism

SREBP-1a

_______ regulates FA metabolism

SREBP-1c

SREB activation in ER

• SREBP binds Scap (cleavage activating protein)

• Silent when cholesterol increased

SREBP activation in golgi

1. Transport proteins (Sec23, Sec24, Sar1) bring proteins to the golgi

2. S1P and S2P (proteases) cleave off bHLH region of SREBP

3. Dimerizes

4. Promotes transcription of target genes for lipid metabolism

bHLH and CTD of SREBP located in the _____

cytosol

SCAP is a ____ in the ___

Cholesterol sensor, ER

Transmembrane units _____ of SCAP bind cholesterol

2-6

______ prevents activation of transcription factor (SREBP) in the presence of ____

Insig-1, sterols

In the absence of sterols, Insig-1 is ___ and _____ by the ____ pathway, and SREBP activation moves forward through _______

removed, degraded, ubiquitin, migration to Golgi

2 types of miRNA, which are cotransported with the ______ gene

miR-33a, miR-33b, SREBP