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Week 13- SHANE > Cholesterol > Flashcards

Cholesterol Flashcards

1
Q

Cholesterol is a precursor for what classes of biologically active compounds?

A

1) Bile acids
2) Steroid hormones
3) Vitamin D

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2
Q

What contributes more to daily cholesterol, dietary intake or endogenous production?

A

endogenous production from bile production (800-1200 mg/day) and intestinal turnover (300 mg) contribute much more than dietary intake (300-500 mg/day) from meat, eggs, and dairy products

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3
Q

Describe the composition of cholesterol

A

Consists of 4 fused rings with a hydroxyl group and ampiphatic hydrocarbon side chain

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4
Q

How does cholesterol align itself in a phospholipid membrane?

A

the polar hydroxyl group arranges itself near the polar heads of the membrane and the ampiphatic tail positions itself facing the interior of the membrane

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5
Q

Is cholesterol soluble in water?

A

Very poorly

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6
Q

Most circulating cholesterol exists in what form?

A

~70% are esterified to fatty acids forming cholesteryl esters (which makes it even more water insoluble)

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7
Q

How is cholesterol transported through the blood given that it is so lipophilic?

A

Circulating cholesterol is transported in lipoprotein particles with free cholesterol on the surface and cholesteryl esters in the hydrophobic core

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8
Q

How is free cholesterol absorbed from the intestinal lumen (note that any cholesteryl esters in the diet will be broken down to free fatty acids and cholesterol before transporting across the lumen)?

What is the inhibitor of the transport enzyme?

A

They form miscelles using bile acid that make them more soluble to be able to cross an ‘unstirred water barrier’ that exits on the apical surface of enterocytes and are then transported into the cell by NPC1L1 (knockout of this gene is only 70%, indicating that there are some other minor pathways).

Inhibitor of NPC1L1= ezetimibe

max expression of NPC1L1 in proximal jejunem

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9
Q

Once inside an enterocyte, what are the fates of free cholesterol?

A

1) they can be (re)esterified to cholesteryl ester by ACAT2 and then packaged by the protein microsomal triglyceride protein (MPT) with APOB48 into chylomicron particles to enter lymph
2) or a heterodimer (have to be dimerized to function!) composed of ABCG5 and ABCG8 that act as the gatekeeper can work to exclude a portion of absorbed cholesterol and relay it back to the intestinal lumen (plant sterols are normally completely excluded by this dimer)

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10
Q

How were ABCG5 and ABCG8 discovered?

A

looking at patients with sitosterolemia (mutations in either cause this disease)

NOTE: ABCG5= ATP binding cassette transporter

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11
Q

Where are ABCG5 and ABCG8 expressed?

A

enterocyte millivilli membrane and in hepatocyte canalicular membrane where they help put/secrete cholesterol into bile (their other function)

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12
Q

How could plant sterols work to lower serum cholesterol (e.g. Benecol)?

A

they could displace cholesterol from micelles which causes them to not be absorbed

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13
Q

What is the major site of cholesterol synthesis?

A

the liver (although the small intestine, adrenal gland, and gonads can make some)

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14
Q

What is the initial substrate of cholesterol?

A

Acetyl CoA is the initial substrate and source of all 27 carbons of cholesterol

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15
Q

Where does the acetyl CoA for cholesterol synthesis come from?

A

1) Long-chain fatty acid B-oxidation
2) Dehydrogenation of pyruvate
3) Oxidation of ketogenic amino acids

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16
Q

Where does the reducing power for cholesterol synthesis come from?

A

NADPH

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17
Q

Where does the energy for cholesterol synthesis come from?

A

ATP (takes a lot!)

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18
Q

How much ATP and NADPH during cholesterol synthesis require?

A

Production of 1 mole of cholesterol requires 18 moles acetyl CoA, 36 moles ATP and 16 moles NADPH

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19
Q

What are the first three steps of cholesterol synthesis?

A

1) 2 acetyl CoA to acetoacetyl CoA (via acetoacetyl CoA thiolase)- gives off CoASH
2) acetoacetyl CoA to HMG CoA (via HMG synthase)- uses acetyl CoA and gives off CoASH

3) HMG CoA to mevalonate (via HMG CoA reductase)- uses 2 NADPH + 2H+ and gives off 2 NADP+ and CoASH

20
Q

What is the committed step of cholesterol synthesis?

A

HMG CoA Reductase making mevalonate (this is the principal site of regulation of cholesterol synthesis)

21
Q

What is HMG CoA reductase inhibited by?

A

Inhibited by the “statin” class of drugs used to treat hypercholesterolemia

22
Q

Transcriptional regulation of HMG CoA reductase occurs by what?

A

SREBP

23
Q

What factors influence HMG CoA reductase activity?

A

1) Intracellular concentration of HMG CoA
2) Intracellular concentration of free cholesterol
3) Hormones: insulin (+), glucagon (-), thyroid hormone (+), cortisol (-) via changes in phosphorylation

24
Q

How is intracellular cholesterol regulated?

A

high levels of intracellular cholesterol can down regulate LDL surface receptors that are responsible for internalizing cholesterol

25
Q

What is a Liver-X receptor (LXRs)?

A

they are ‘nuclear’ receptors, meaning that they moderate uptake of cholesterol from the bloodstream and can also leave the cell surface and go into the nucleus to influence transcription of relevant genes

26
Q

Where are LXR-a typically found?

A

abundant in the liver and other tissues, including intestine (most important one)

27
Q

Where are LXR-B typically found?

A

very common in many tissues (more ubiquitous)

28
Q

What is unique about LXR-a regulates itself?

A

it has an LXR response element in its promoter gene and can auto-regulate its own transcription

29
Q

What are LXRs stimulated by?

A

oxysterols (oxidized cholesterol that are often found in small amounts but are good regulators)

30
Q

How do LXRs work?

A

LXR has a ligand binding site along with a DNA binding site. When oxysterol binds, it dimerizes with RXR (which also has a ligand binding site- substrate is cis-retinoic acid (usually abundant and not rate-limiting) and a DNA binding site) and together they bind to a promoter gene to influence transcription of many genes involved in cholesterol synthesis and transport

generally works to prevent cholesterol overload by down-regulating receptors and transporters

31
Q

What is Smith-Lemli-Optiz Syndrome?

A

deficiency in an enzyme used to synthesize cholesterol resulting in low cholesterol plasma levels and high (toxic) levels of the pre-cursor that cannot be processed (affects the brain)

Leads to cataracts, hypotonia, growth retardation, etc. (highly variable)

32
Q

What are bile acids made from?

A

cholesterol in the liver and are conjugated to the AAs taurine and glycine to increase solubility and ability to form micelles

33
Q

What is the primary function of bile acids?

A

Secreted in bile and act as detergents to emulsify the products of fat digestion to form micelles to facilitate transport across the unstirred water layer to enter the enterocyte

34
Q

Where are bile acids absorbed after working?

A

in the distal ileum through an active transport process where they enter enterohepatic circulation

35
Q

What is the rate limiting step in bile acid synthesis?

A

Cholesterol 7 a-hydroxylase (CYP7A1) is rate-limiting enzyme in bile acid synthesis

36
Q

What regulates production of bile acids?

A

Regulation via farnesoid X receptor (FXR) that binds bile acids and down-regulates CYP7A1 transcription

FXR can also have effects on lipid metabolism and inflammation

37
Q

What are the primary bile acids produced by the liver?

A

1) glycocholic acid
2) taurocholic acid
3) glycochenodeoxycholic acid
4) taurochenodeoxycholic acid

38
Q

What happens to the primary bile acids?

A

in the lumen of the gut they are acted on by bacteria and made into secondary bile acids which are not conjugated (can be toxic if accumulated- rarely happens)

39
Q

What are the steps of enterohepatic circulation of bile acids?

A

1) the liver synthesizes about 0.2-0.6g of bile acids a day and they are stored in the gallbladder as a component of bile
2) when you eat, cholycystichymine (a GI hormone) is stimulated to be released and makes the gallbladder contract and bile enters the duodenum where it forms micelles and helps absorb fat
3) once done, it moves to the ileum where ~95% is reabsorbed into the portal venous blood to be transported back to the liver
4) some (0.2-0.6g) is excreted in stool (the only excretory pathway for cholesterol)
5) cycle contains 4-12 cycles a day

40
Q

What is Chron’s disease?

A

affects the ileum (causes inflammation) and causes increased loss of bile acids in stool. If the reservoir of bile acids diminishes, fat absorption becomes hindered. (the liver can up regulate production but it may not be enough)

41
Q

What is the transporter of bile acids into the ileocytes and colonocytes for reabsorption into enterohepatic circulation?

A

ASBT (so the colon uptake is NOT passive)

kidney re-uptake also involves ASBT and is not passive either

42
Q

What is the transporter of bile acids OUT of the ileocytes and colonocytes for reabsorption into enterohepatic circulation?

A

OST (organic solute transporter)- puts bile acids into portal blood to go back to the liver

‘NTCP’ is the receptor on the liver that takes bile acids from the portal blood into the liver to complete recirculation

43
Q

What does fibroblast growth factor 19 (FGF19) do?

A

regulated by FXR. FXR moves in portal blood and attaches to a receptor on the liver surface and through a MAP/ERP pathway, inhibits bile acid synthesis

‘SHP’ does the same thing. Reabsorbed bile acids can up-regulate these proteins

44
Q

How are gallstones formed?

A

bile is composed of bile acids, cholesterol, and phospholipids. Normally, there is a lot of bile acids and phospholipids and not much cholesterol, and the bile is liquid in ‘Phase 1’. But if the equilibrium is disturbed (i.e. more cholesterol or less of the other two), the bile can crystallize and form gallstones

45
Q

How do you treat gallstones?

A

Actigall (ursodeoxycholic acid)- a water soluble bile acid that prevents precipitation of bile stones. Giving this to humans causes the gallstones to be dissolved

Week 13- SHANE (12 decks)

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