Dietary cholesterol

De novo synthesis in liver

cholesterol synthesized in extrahepatic tissues

Conversion to bile acids/salts

Free cholesterol secreted in bile

Secretion of HDL and VLDL

3-hydroxy-3-methylglutaryl-CoA (HMG CoA) converted to mevalonate

The enzyme is HMG CoA reductase (as opposed to HMG CoA lyase which is used in liver mito. to make ketone bodies)

Reaction occurs in the cytosol of liver cells

Requires 2 NADPH

It is the rate-limiting and committed step

Irreversible rxn

HMG CoA reductase is the target of a class of cholesterol-lowering drugs known as statins

1) HMG CoA converted to mevalonate by HMG CoA reductase - regulated step which is committed and rate-limiting

2) mevalonate (a 5C compound) is converted to isopentyl pyrophosphate (a 5C compound) which is considered a building block for cholesterol

3) isopentyl pyrophosphate (IPP) isomerizes to 3,3-dimethyallyl phosphate (DPP) and the DPP condenses with another IPP to form geranyl pyrophosphate (a 10C)

4) GPP condenses with another IPP to form farnesyl pyrophosphate (FPP, 15C)

5) Two molecules of FPP combine and release pyrophosphate and form squalene (30C)

6) Squalene is converted to lanosterol in a series of reactions

7) Lanosterol (30C) is converted to cholesterol (C27) in a series of reactions

1) Phosphorylation of mevalonate to phosphomevalonate

2) Phosphorylation of phosphomevalonate to pyrophosphomevalonate

3) Decarboxylation of pyrophosphomevalonate to isopentyl pyrophosphate (ATP is used as energy to drive the rxn, no phosphorylation occurs)

Since 6 isopentyl pyrophosphates are used to make one molecule of cholesterol, 18 ATP's are required. Cholesterol synthesis is very energy intensive!

1) Conversion of HMG CoA to mevalonate uses 2 NADPH - the committed and rate-limiting step

2) Combining of two farnesyl pyrophosphates (15 C) uses 1 NADPH

Because 6 HMG CoA's are used for one molecule of cholesterol (remember 6 isopentyl pyrophosphates), 13 NADPH is required

HMG CoA reductase is inhibited by phosphorylation - the inactive form of the enzyme is phosphorylated

AMP-dependent kinase phosphorylates HMG CoA reductase to inactivate the enzyme

HMG CoA reductase phosphatase removes the phosphate group to activate it

These two enzymes are regulated by things like AMP and ATP, glucagon and EPI, and insulin

low energy (high AMP) --> low synthesis

A high AMP/ATP ratio inhibits HMG CoA reductase - cells do not want to synthesize cholesterol if they do not have enough energy

AMP activates AMP dependent kinase

AMP dependent kinase inactivates HMG CoA reductase through phosphorylation

Insulin increases cholesterol synthesis

insulin activates protein phosphatase 2C which deactivates AMP dependent kinase and keeps HMG CoA reductase in its active dephosphorylated state

insulin also activates phosphoprotein phosphatase which deactivates phosphoprotein inhibitor 1 (PPI-1)

PPI-1 inhibits HMG CoA reductase phosphatase from activating HMG CoA reductase so decreased PPI-1 leads to increased HMG CoA reductase phosphatase which leads to increased activated HMG CoA reductase and thus increased cholesterol synthesis

Glucagon and EPI decrease cholesterol synthesis

They cause increased levels of cAMP which lead to increased PKA activity

PKA activates PPI-1

PPI-1 inhibits HMG CoA reductase phosphatase

This keeps HMG CoA reductase in its phoshphorylated inactive state

Thus cholesterol synthesis is decreased

1) conversion to bile acids (secreted in feces)

2) secretion into bile as free cholesterol (transport to intestine)

REMEMBER the ring structure of cholesterol is not metabolized

Primary bile acids

1) cholic acid

2) chenodeoxycholic acid

Secondary bile acids

1) deoxycholic acid

2) lithocholic acid

These four bile acids can be conjugated with either glycine or taurine thus there are 4 types of primary bile acids

The introduction of a hydroxyl group at C7 of the cholesterol to form 7-alpha-hydroxycholesterol

The enzyme is 7-alpha-hydroxylase

The reaction uses NADPH and O2 and requires Vit C as a co-factor

Product inhibition occurs with the bile acids - the bile acids decrease the level of 7-alpha-hydroxylase by inhibiting the transcription of its gene

Cholesterol converted to 7-alpha-hydroxycholesterol by 7-alpha-hydroxylase - rate-limiting step

7-alpha-hydroxycholesterol converted to Choyl CoA or Chenodeoxychoyl CoA in several steps

The CoA's can be conjugated with glycine or taurine to form primary bile acids

Primary bile acids undergo deconjugation and reduction in the small intestine to form secondary bile acids

Bile acids decrease the level of 7a-hydroxylase by inhibiting the transcription of its gene.

increased liver cholesterol levels will induce 7a-hydroxylase gene transcription while decreasing HMG-CoA reductase activity.

Bile acids decrease HMG-CoA reductase activity.

Bile acids are physiological ligands for the nuclear bile acid-binding receptor farnesoid X receptor (FXR).

When the bile pool increases, FXR is activated and transcription of 7a-hydroxylase is repressed through induction of small heterodimer protein (SHP‑1).

Thyroid hormone, insulin, glucagon, and glucocorticoids regulate the expression of 7a-hydroxylase.

0.3 - 0.5 grams of cholesterol (from the blood and de novo synthesis) per day is converted to bile acids in the liver, forming the bile acid pool

15 - 30 g/day of bile acids is secreted to the small intestine through the bile duct

Some of the primary bile acids present undergo reduction and deconjugation to form secondary bile acids

0.3 - 0.5 g/day of primary and secondary bile acids is excreted as feces

15 - 30 g/day of primary and secondary bile acids is reabsorbed by the liver through the portal vein (thus the bile acid pool is primary and secondary)

Gallstones form when bile stored in the gallbladder hardens into stone-like material. The size of gallstones varies from a grain of salt to golf-ball size. A person can develop a single stone or several hundred.

In fact, gallstones often cause no symptoms and require no treatment. But some people with gallstones will have symptoms such as nausea and an intense, steady ache in their upper middle or upper right abdomen. In some cases, the pain can be severe and intermittent.

Gallstones that obstruct bile ducts can lead to a severe or life-threatening infection of the bile ducts, pancreas, or liver.

Gallstones affect as many as one in 12 Americans.

Two types - cholesterol stones and pigment stones

Cholesterol stones form when bile contains too much cholesterol, not enough bile salts, or when the gallbladder does not empty as it should. Normally, your bile contains enough bile salts and lecithin to dissolve the cholesterol excreted by your liver. But if your bile contains more cholesterol than can be dissolved, the cholesterol may form into crystals and eventually into stones.

Cholesterol in your bile has NO relation to the levels of cholesterol in your blood, and cholesterol-lowering drugs don't help prevent gallstones.

1. surgical removal of the gall bladder (cholecystectomy) - must be followed by strict restriction of fat intake

2. oral intake of bile acids (ursodeoxycholic acid or chenodeoxycholic acid)

3. direct perfusion of gall bladder with organic solvents (methyl t-butyl ehter)

4. fragmentation by lithotripsy - using shock waves to break up the stones into smaller fragments