Section 4: Part 7 - Cholesterol Metabolism

cholesterol

most abundant steroid in mammals

cholesterol is clarified as a ____________ due to its C3-OH group

sterol

cholesterol is ______________________ due to its ______________ group

weakly ampiphiilc; polar OH

cholesterol has a ___________________ that provides __________________ than other

membrane lipids

fused ring system; greater rigidity

what is cholesterol important for?

cell membranes

what is cholesterol a precursor for?

steroid hormones and bile acids

cholesterol's _____________________ is associated with cardiovascular disease and stroke

deposition in arteries

cholesterol synthesis (in liver)

- 2 acetyl-CoA --> Acetoacetyl-CoA

- Acetyl-CoA + Acetoacetyl-CoA --> (HMG-CoA)

Cholesterol - Synthesis

What enzymes are involved?

(1) Thiolase

(2) HMG CoA synthase

Where does ketogenesis occur?

mitochondria

Synthesis of HMG-CoA for cholesterol synthesis occurs in _______________

cytosol

Cholesterol biosynthesis depends on export of acetyl-CoA from ______________________

mitochondria

Cholesterol synthesis requires ________________

NADPH

Isopentenyl pyrophosphate synthesis - Step 1

HMG-CoA --> Mevalonate (C6)

Isopentenyl pyrophosphate synthesis - Step 2

Mevalonate --> Phosphomevalonate

Isopentenyl pyrophosphate synthesis - Step 3

Phosphomevalonate --> 5-Pyrophosphomevalonate

Isopentenyl pyrophosphate synthesis - Step 4

5-Pyrophosphomevalonate --> Isopentenyl-pyrophosphate

What intermediates are formed in Isopentenyl pyrophosphate synthesis?

C10, C15, and C30 intermediate

Farnesyl pyrophosphate (C15)

Precursor of other isoprenoid compounds

Farnesyl pyrophosphate (C15) is also involved in ______________________________ of some membrane-associated proteins

posttranslational modification

Inhibitory drugs like __________ inhibit Farnesyl pyrophosphate synthesis

statins

Squalene cyclization --> Sterol intermediate

Squalene epoxidase reaction and Oxidosqualene cyclase reaction

Lanosterol --> Cholesterol

•Demethylation, desaturation and saturation

• 19-step process

• Enzymes required for the process are embedded in

the ER membrane

Liver converts cholesterol to ____________

bile acids

bile acids

emulsifying agents in the digestion and absorption of fats

cholesterol is a precursor for

steroid hormones

Bile acids re-enters the bloodstream and return to _________ for reuse several times each day

liver

Bile acids that escape recycling are further _________________________________(only route for cholesterol excretion)

metabolized by intestinal microorganisms and excreted

Cholesterol synthesized by the liver may be esterified by acyl-CoA:cholesterol acyltransferase (ACAT) to form ___________________________

cholesteryl esters

HMG-CoA reductase

key enzyme in cholesterol biosynthesis

Key elements for transcriptional control

• Sterol response element (SRE)

• SRE-binding protein (SREBP)

• SREBP cleavage activating protein (SCAP)

Sterol response element (SRE)

DNA consensus sequence that controls the transcription of HMG-CoA reductase

SRE-binding protein (SREBP)

- initially embedded in the ER membrane

- unable to bind SRE

- bound to SCAP

SREBP cleavage activating protein (SCAP)

cholesterol sensor

What happens when cholesterol is high?

- SCAP binds to third protein INSIG

- Ternary complex is rapidly degraded

What happens when cholesterol is low?

- SCAP changes conformation

- SCAP-SREBP complex binds to membrane proteins of COPII-coated vesicles

- Vesicles bud off from ER and travel to Golgi apparatus

SREBP cleaved sequentially by two Golgi proteases

site 1 and site 2 protease

site-1 protease (S1P)

cleaves SREBP only when it is associated with SCAP

site-2 protease (S2P)

cleaves SREBP at a peptide bond exposed by the S1P cleavage

SREBP proteolysis

release of the active fragment

Active fragment

travels to the nucleus and activates the transcription of genes containing SRE

HMG-CoA reductase transcription

Cholesterol level rises until SCAP no longer induces the translocation of SREBP to the Golgi apparatus

HMG-CoA reductase role

facilitates the negative feedback regulation imposed by cholesterol

statins

Bind HMG-CoA tighly and are used to treat hypercholesterolemia

Statins purpose

reduce LDL cholesterol levels

Atherosclerosis

Elevated cholesterol level - primarily in the form of LDL - in the blood

What can Atherosclerosis lead to?

CV disease

Atherosclerosis begins with the _____________________ in the walls

of coronary arteries

deposition of lipids

atherosclerotic lesion - stage 1

Formation of defects in endothelium

atherosclerotic lesion - stage 2

Magrophages turn into foam cells

atherosclerotic lesion - stage 3

Formation of crystalline deposits

atherosclerotic lesion - stage 4

Cell proliferation and thrombusformation

Myocardial infarct & stroke

plaque undergoes calcification, leading to hardening of arteries

Rupture can trigger formation of blood clot preventing circulation to heart can cause __________________________

myocardial infarction (heart attack)

Stoppage of blood flow to the brain causes ________________

stroke

The development of atherosclerosis is strongly correlated with the concentration of _________

circulating LDL

risk factors for high LDL

- high-fat diets

- genetic factors

- infection

- smoking

what does smoking do?

smoke oxidizes LDL which promotes their uptake by macrophages

Risk of atherosclerosis decreased by:

- low total cholesterol levels in blood

- high levels of HDL

Why do women have lower risk of heart disease compared to men?

they have more HDL

HDL purpose

transport excess cholesterol to the liver for disposal as bile acids

Individuals deficient in functional LDL receptors:

have extremely high levels of LDL, and cholesterol deposits in their skin as yellow nodules (xanthomas)

What transport protein can help eliminate cholesterol?

ATP-cassette binding protein A1 (ABCA1)

Tangier disease

Cells have defective ABCA1 so almost no HDL is produced

ABCA1 acts as a ___________________ in normal people

flippase