Cholesterol Synthesis and Transport

Question 1

Summary of cholesterol synthesis and transport

Answer 1

acetyl-CoA is converted to mevalonate using HMG CoA reductase. Mevalonate is converted to 3-isopentyl pyrophosphate to cholesterol, which inhibits the synthesis of HMG CoA reductase, to vitamin D, bile salts, or steroid hormones through transport by VLDL, LDL, or HDL

Question 2

Structure of cholesterol

Answer 2

4 rings, 27 carbons (all derived from actyl-CoA)

Question 3

Cholesterol synthesis stages

Answer 3

Stage 1 - Synthesis of isopentyl pyrophosphate
Stage 2 - 6 isopentyl pyrophosphate to squalene
Stage 3 - Squalene cyclizes and converts to cholesterol

Question 4

What is the rate limiting step of cholesterol synthesis?

Answer 4

3-Hydroxy-3-methylglutaryl-CoA converted to mevalonate by HMG-CoA reductase

Question 5

What does HMG CoA synthase do?

Answer 5

It converts acetoacetyl CoA to beta-hydroxy-beta-methyl-glutaryl CoA or HMG-CoA using acetyl CoA.

Question 6

What are the two types of HMG-CoA synthase?

Answer 6

mitochondrial and cytoplasmic

Question 7

In the mitochondrion, HMG CoA synthase makes ___, but in cytosplasmic HMG CoA synthase produces ____.

Answer 7

ketone bodies,

cholesterol

Question 8

Statins inhibit ____.

Answer 8

HMG-CoA reductase

Question 9

____ and ___ are potential side effects of statins.

Answer 9

Rhabdomyolysis and myopathy

Question 10

What are some statins?

Answer 10

Compactin, Simvastatin (Zocor), Pravastatin (Pravachol) and Lovastatin (Mevacor)

Question 11

Statins are ___ inhibitors that resemble ____.

Answer 11

competitive, mevalonate

Question 12

Statins lower ____.

Answer 12

Plasma cholesterol levels (>50%)

Question 13

What molecules are downstream of mevalonate?

Answer 13

Cholesterol, ubiquinone/CoQ, Vitamin D, Bile salts, and steroid hormones

Question 14

What are the enzymes involved in the reactions that occur after mevalonate is produces?

Answer 14

Mevalonate 5’ phosphokinase, phosphomevalonate kinase, and pyrophosphomevalonate decarboxylase

Question 15

What are the steps between isopentenyl pyrophosphate and squalene?

Answer 15

isopentenyl pyrophosphate and dimethylallyl pyrophosphate combine to form geranyl pyrophosphate (a 10C) which forms farnesyl pyrophosphate (15 C polyisoprene), which combine to form a squalene (30C polyisoprene)

Question 16

Steps of squalene cyclization

Answer 16

Squalene to squalene epoxide to ianosterol to cholesterol

Question 17

How is the synthesis of cholesterol regulated?

Answer 17

insulin activates HMG-CoA reductase. Glucagon and high levels of intracellular cholesterol inhibit HMG-CoA reductase (as well as mevalonate). Cholesterol stimulates proteolysis of HMG-CoA reductase.
HMG-CoA reductase is active when dephosphorylated.

Cholesterol activates ACAT, which creates cholesteryl esters.
high levels of cholesterol also inhibit receptor-mediated endocytosis of LDL-cholesterol (extracellular)

Question 18

HMG-CoA reductase is transcribed by ___.

Answer 18

SREBP (Sterol regulatory element-binding protein)

Question 19

What are major sites of cholesterol synthesis?

Answer 19

The liver and intestine

Question 20

Explain the regulation of HMG-CoA reductase

Answer 20

Sterol binding prevents transport (of SCAP?) to golgi
Proteolysis occurs in the golgi, which releases SREBP DNA binding domain.
Transcription of the reductase gene in nucleus

Question 21

SREBP

Answer 21

Sterol regulatory element-binding protein

Question 22

SCAP

Answer 22

SREBP cleavage-activating protein; binds cholesterol and other sterols - moves to golgi in the absence of cholesterol binding

Question 23

Products of activated isoprenes (products of 3-isopentenyl pyrophosphate)

Answer 23

Vitamins A,D,E,K, steroid hormones, Quinone electron carriers (ubiquinone, plastoquinone), bile acis, carotenoids, isoprene, phytol chain of chlorophyll, rubber, plant hormones, dolichols

Question 24

Where are bile acids synthesized?

Answer 24

in the liver

Question 25

What is the difference between cholesterol and bile acids?

Answer 25

Hydroxylation of the seventh carbon on cholesterol using 7-alpha-hydroxylase

Question 26

What is the rate limiting step in the production of bile acis?

Answer 26

Hydroxylation of the seventh carbon on cholesterol using 7-alpha-hydroxylase

Question 27

What are some possible products of bile acids?

Answer 27

Bile salts (glycine or taurine can be added to bile acids)

Question 28

7-alpha-hydroxylase is inhibited by ___.

Answer 28

bile salts

Question 29

Bile salts are deconjugated by ___ and become ___.

Answer 29

bacteria, | secondary bile salts (that's what 2 knot is right?)

Question 30

Bile contains ___.

Answer 30

water, cholesterol, bile salts, and bilirubin

Question 31

Cholesterol is solubilized by ____.

Answer 31

Phospholipids and bile salts

Question 32

Cause of gallstones

Answer 32

cholesterol stones that block flow of bile factors: 1) Bile acid levels, 2) biliary cholesterol secretion, and 3) gallbladder hypomotility

Question 33

Gallstones occur more frequently _____.

Answer 33

In females, for Mexican americans, with obesity or metabolic syndromes where cholesterol is increased (and there is a normal bile acid pool) with increasing age (due to decreased bile acid pool) with gall bladder hypomotility caused by fasting or pregnancy with rapid weight loss (due to fasting) and due to genetic defects in the CYP7A1 gene that converts cholesterol to bile acids

Question 34

Cholesterol esters are transported in the blood as ___.

Answer 34

A fatty acid ester

Question 35

What is lecithin?

Answer 35

it uses phosphatidyl choline. It is a cholesterol actyltransferase (or LCAT) that esterifies HDL cholesterol It generates cholesterol esters from phosphatidylcholine and cholesterol and is taken from chylomicron and VLDL remnants

Question 36

What is ACAT?

Answer 36

Acyl:cholesterol acylransferase. It is intracellular and packages cholesterol for VLDL and storage in liver for bile production

Question 37

What does CETP do?

Answer 37

Cholesterol ester transfer protein transfers cholesterol from HDL to VLDL. (Inhibiting CETP raises HDL)

Question 38

What are the plasma lipoprotein particles?

Answer 38

Chylomicrons, VLDL, LDL, and HDL

Question 39

What is necessary to know about chylomicrons?

Answer 39

They transport dietary triglycerides. They are synthesized in the epithelial cells of the intestine. They are the least dense plasma lipoprotein and the highest triglyceride (density) They use ApoB-48 which is unique to chylomic and ApoC-II (that activates lipases) When chylomicron remnants are depleted of triglycerides, ApoE is exposed and binds to receptors on the liver and cholesterol is released.

Question 40

What is necessary to know about VLDL?

Answer 40

Very low density lipoprotein transports endogenous triglycerides. Excess fatty acid made from carbohydrates that are not needed for fuel are converted into triglycerides in the liver and packaged with apolipoproteins and into VLDL particles. They contain cholesterol and cholesterol ethers ApoB-100 (receptor recognition domain is not expose), ApoC-II, ApoE 50% of VLDL remnants are removed via ApoE receptor mediated endocytosis in liver, 50% VLDL forms IDL, then LDL

Question 41

What is necessary to know about LDL?

Answer 41

Low density lipoprotein is used to transport cholesterol to tissues It is very rich in cholesterol and cholesterol esters. ApoB-100 is used (receptor recognition domain is exposed) They carry cholesterol to extrahepatic tissues (e.g. gonadal cells for steroid synthesis) Receptor-mediated endocytosis recognizes ApoB-100 "bad cholesterol"

Question 42

What is necessary to know about HDL?

Answer 42

High density lipoprotein is the "good cholesterol" and performs reverse cholesterol transport (tissue to liver) It originates in the liver or small intestine Nascent HDL has very little cholesterol ApoA-I activates LCAT, ApoC-II and ApoE also used Lecithin-cholesterol acyl transferase (LCAT) is acquired from blood stream. It generates cholesterol esters from phosphatidylcholine and cholesterol and is taken from chylomicron and VLDL remnants. HDL particle binds scavenger receptor-B1 and unloads cholesterol to liver

Question 43

A deficiency of an LDL receptor causes ___.

Answer 43

High blood cholesterol

Question 44

LDL receptors recognize ___ and bind ___.

Answer 44

ApoE and ApoB-100, | VLDL, IDL, LDL, and chylomicron remnants

Question 45

LRP or LDL receptor related protein is found in _____ and binds ____. Expression is independent of ____ and increases in response to ____.

Answer 45

the liver, brain, and placenta, ApoE, cholesterol concentration, insulin

Question 46

How do scavenger receptors work?

Answer 46

SR-B1 binds HDL | SR-A1, SR-A2 on macrophages bind oxidized LDL (superoxide). Expression is independent of cholesterol concentration

Question 47

What are foam cells?

Answer 47

They are macrophages engorged with lipid

Question 48

HDL is cleared primarily through ___.

Answer 48

SR-B1 receptors

Question 49

What is familial hypercholesterolemia?

Answer 49

It is a disease in which a person has a defective LDL receptor. The absence of LDL receptor prevents uptake of LDL cholesterol and stimulates continued synthesis of cholesterol. There LDL concentration is about 200-400 mg/dL in heterozygotes and 500-800 mg/dL in homozygotes. There is a high incidence of coronary artery disease. Xanthomas, or deposition of cholesterol rich material on tendons, occurs in heterozygous adults and homozygous children. A corneal arcus, or white line on the edge of cornea) appears in homozygous children.

Question 50

What is FLDB?

Answer 50

Familial Ligand Defective ApoB-100 has similar symptoms as familial hypdercholesterolemia, but not as severe. ApoE also recognizes LDL receptor, so VLDL and IDL uptake is normal.

Question 51

How are LDL receptors involved in cholesterol regulation?

Answer 51

Increased cholesterol down regulates the LDL receptor (transcription) Low intracellular cholesterol increases LDL receptor synthesis and signals continued cholesterol synthesis. ACAT (Acyl:cholesterol acylransferase) is stimulated to make cholesterol esters for storage

Question 52

What is Tangier Disease?

Answer 52

It is a rare metabolic disorder (only 100 cases identified) that revealed the role of ABC transporters in HDL metabolism. There are extremely low levels of HDL. Cholesterol accumulates in macrophages ABC A1 is defective in Tangier disease. Normally it transports cholesterol out of macrophages into HDL and is in the ATP cassette family of transporters

Question 53

_____ and ____ form a heterodimer transcriptional activator complex upon binding oxysterols such as 25-hydroxycholesterol

Answer 53

Liver X Receptor (LXR) and retinal X receprot (RXR)

Question 54

Expression of ___ and ____ are activated when cholesterol levels are high (and therefore oxysterols are high)

Answer 54

CETP (Cholesterol ester transfer protein) and ABCA1

Question 55

What are ways to treat high LDL?

Answer 55

Restricted diet - reduced cholesterol, red meat, increased fruit, vegetables, fish, and whole grains. 10-25% reduction. Mediterranean diet reduced 30%. HMG CoA Reductase inhibitors (statins) - inhibit cholesterol biosynthesis. Results in lower intracellular cholesterol which stimulates synthesis of LDL receptors and pulls more cholesterol from circulation. Lowers total and LDL cholesterol 30% reduction in cardiovascular death for patients with CHD Bile acid excretion - Cholesteryarmine binds negatively charged bile acids in small intestine, increases bile excretion Cholesterol convered to bile acids Lowers total and LDL cholesterol Eztimibe (Zetia) blocks cholesterol absorption into the intestinal cells. Lowers LDL. Decreased use. Fibrates - agonists of PPARalpha, a nuclear transcription factor. It activates synthesis (transcription) of many proteins in lipid metabolism eg. lipoprotein lipase, apoA1 (HDL) It increases proteins and leads to enhanced utilization offat and reduction in lipoprotein particles It lowers triglycerides (30%) and total and LDL cholesterol (10-15%) Nicotinic Acid - Clinical benefit is questioned. Increases HDL levels. High oral doses inhibit hormone sensitive lipase in adipose tissue, reducing plasma triacylglycerol, thus reducing VLDL synthesis by live. Facial flushing is side effect.

Question 56

Examples of statins

Answer 56

Lovastatin, pravastatin, simvastatin, fluvastatin, and atorvastatin

Question 57

Examples of fibrates

Answer 57

fenofibrate, gemfibrazil