Flashcards in Cholesterol Synthesis and Transport Deck (57):
Summary of cholesterol synthesis and transport
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
Structure of cholesterol
4 rings, 27 carbons (all derived from actyl-CoA)
Cholesterol synthesis stages
Stage 1 - Synthesis of isopentyl pyrophosphate
Stage 2 - 6 isopentyl pyrophosphate to squalene
Stage 3 - Squalene cyclizes and converts to cholesterol
What is the rate limiting step of cholesterol synthesis?
3-Hydroxy-3-methylglutaryl-CoA converted to mevalonate by HMG-CoA reductase
What does HMG CoA synthase do?
It converts acetoacetyl CoA to beta-hydroxy-beta-methyl-glutaryl CoA or HMG-CoA using acetyl CoA.
What are the two types of HMG-CoA synthase?
mitochondrial and cytoplasmic
In the mitochondrion, HMG CoA synthase makes ___, but in cytosplasmic HMG CoA synthase produces ____.
Statins inhibit ____.
____ and ___ are potential side effects of statins.
Rhabdomyolysis and myopathy
What are some statins?
Compactin, Simvastatin (Zocor), Pravastatin (Pravachol) and Lovastatin (Mevacor)
Statins are ___ inhibitors that resemble ____.
Statins lower ____.
Plasma cholesterol levels (>50%)
What molecules are downstream of mevalonate?
Cholesterol, ubiquinone/CoQ, Vitamin D, Bile salts, and steroid hormones
What are the enzymes involved in the reactions that occur after mevalonate is produces?
Mevalonate 5' phosphokinase, phosphomevalonate kinase, and pyrophosphomevalonate decarboxylase
What are the steps between isopentenyl pyrophosphate and squalene?
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)
Steps of squalene cyclization
Squalene to squalene epoxide to ianosterol to cholesterol
How is the synthesis of cholesterol regulated?
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)
HMG-CoA reductase is transcribed by ___.
SREBP (Sterol regulatory element-binding protein)
What are major sites of cholesterol synthesis?
The liver and intestine
Explain the regulation of HMG-CoA reductase
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
Sterol regulatory element-binding protein
SREBP cleavage-activating protein; binds cholesterol and other sterols - moves to golgi in the absence of cholesterol binding
Products of activated isoprenes (products of 3-isopentenyl pyrophosphate)
Vitamins A,D,E,K, steroid hormones, Quinone electron carriers (ubiquinone, plastoquinone), bile acis, carotenoids, isoprene, phytol chain of chlorophyll, rubber, plant hormones, dolichols
Where are bile acids synthesized?
in the liver
What is the difference between cholesterol and bile acids?
Hydroxylation of the seventh carbon on cholesterol using 7-alpha-hydroxylase
What is the rate limiting step in the production of bile acis?
Hydroxylation of the seventh carbon on cholesterol using 7-alpha-hydroxylase
What are some possible products of bile acids?
Bile salts (glycine or taurine can be added to bile acids)
7-alpha-hydroxylase is inhibited by ___.
Bile salts are deconjugated by ___ and become ___.
secondary bile salts (that's what 2 knot is right?)
Bile contains ___.
water, cholesterol, bile salts, and bilirubin
Cholesterol is solubilized by ____.
Phospholipids and bile salts
Cause of gallstones
cholesterol stones that block flow of bile
factors: 1) Bile acid levels, 2) biliary cholesterol secretion, and 3) gallbladder hypomotility
Gallstones occur more frequently _____.
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
Cholesterol esters are transported in the blood as ___.
A fatty acid ester
What is lecithin?
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
What is ACAT?
Acyl:cholesterol acylransferase. It is intracellular and packages cholesterol for VLDL and storage in liver for bile production
What does CETP do?
Cholesterol ester transfer protein transfers cholesterol from HDL to VLDL.
(Inhibiting CETP raises HDL)
What are the plasma lipoprotein particles?
Chylomicrons, VLDL, LDL, and HDL
What is necessary to know about chylomicrons?
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.
What is necessary to know about VLDL?
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
What is necessary to know about LDL?
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
What is necessary to know about HDL?
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
A deficiency of an LDL receptor causes ___.
High blood cholesterol
LDL receptors recognize ___ and bind ___.
ApoE and ApoB-100,
VLDL, IDL, LDL, and chylomicron remnants
LRP or LDL receptor related protein is found in _____ and binds ____. Expression is independent of ____ and increases in response to ____.
the liver, brain, and placenta,
How do scavenger receptors work?
SR-B1 binds HDL
SR-A1, SR-A2 on macrophages bind oxidized LDL (superoxide). Expression is independent of cholesterol concentration
What are foam cells?
They are macrophages engorged with lipid
HDL is cleared primarily through ___.
What is familial hypercholesterolemia?
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.
What is FLDB?
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.
How are LDL receptors involved in cholesterol regulation?
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
What is Tangier Disease?
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
_____ and ____ form a heterodimer transcriptional activator complex upon binding oxysterols such as 25-hydroxycholesterol
Liver X Receptor (LXR) and retinal X receprot (RXR)
Expression of ___ and ____ are activated when cholesterol levels are high (and therefore oxysterols are high)
CETP (Cholesterol ester transfer protein) and ABCA1
What are ways to treat high LDL?
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.
Examples of statins
Lovastatin, pravastatin, simvastatin, fluvastatin, and atorvastatin