KBKF15 - WEEK 7 - CHOLESTEROL AND INTEGRATION OF METABOLISM

CHAPTER 26 & 27

Phosphatide (PA) : why is it important?

• Key intermediate for phospholipids and triacylglycerol

• PA is formed from glycerol-3-phosphate (G3P), which is primarily formed by DHAP
  

• the reaction is regulated with 1 un/saturated enzyme, so that 2 AA are connected with ester bonds.

Phosphatide (PA) —> Triacylglycerol (TAG)

PA is de-phosphorylated to form TAG. A 3rd FA is activated by CoA, replaces the phosphate group in PA. The reaction happens primarily in the liver cells ER mmembrane.

Phosphatide (PA) —> Phospholipids.

1. A activated intermediate is needed, CTP binds to PA to form CDP diacylglycerol (with hydrolysis).

2. the activated PA then reacts with -OH of alcohol. (We can get PE, PC, PS) depending on the structure of the alcohol.

What is cholesterol?

C₂₇H₄₆O

• Steroid molecule

• Controls about 30% of cell fluidity and bidrar till produktionen av biel salts, steroid hormones and Vit D.

• Both Exogenous and Endogenous
  

• The -OH gives the molecule a charge, and is faced outwards in the membrane.

What are the 3 stages of cholesterol synthsis?

All 27C comes from Acetyl-CoA

1. Synthesis of isopentenyl pyrophosphate in cytoplasm

2. Condensation to squalene in ER

3. convertion to cholesterol in ER

Stage 1 - 3-isopentyl pyrophosphate

1. Acetyl-CoA and Acetoacetyl-CoA (also from acetyl-CoA) forms mevalonate using 2 NADPH, this step is rate limiting and occurs in cytoplasm.

2. Mevalonate is then turned into 3-isopentyl pyrophosphate using 3 ATP.

Stage 2 - squalene synthesis

1. Isomerization of isopentyl pyrophosphate into demetylallyl pyrophospahte. 1 of each is needed to start the reaction.

2. Followed by condensation to form squalene using 1 NADPH.

Stage 3 - Cyclization to form cholesterol

1. Activating of squalene by forming an epoxid with an enzyme that holds squalene in place for e- to jump.

2. Epoxid are super unstable, so reactions happens and finally spontaneous rearrangment to lanosterol upon protonation.

3. then turned into cholesterol in 17 steps.

Regulation of cholesterol biosynthsis - main focus on SREBP

It is a transcription factor that senses the level off presented cholesterol. it has a DNA-binding domain.

• When [Cholesterol] is low, SREBP will move from ER to Golgi, and the DNA-binding domain wil be cleaved and will bind to SRE to enhance gene expression.

• high [Cholesterol] —> cleavage blocked, won’t enter Golgi and no enhencment of expression.

Lipoproteins

Core built by hydrophobic lipids that is surrouded by polar lipids and proteins.

• Important for transport of hydrophobic molecules and cholesterol homeostasis (maintain stable conditions in the cells).

• Classified according to density, different classes has different roles. The class can be shifted by picking / releasing cargos.

What is LDL’s role in cholesterol metabolism?

• They work as the main cholesterol transporters.

• There are specific LDL receptors that can be recycled, the numbers of these increases when the level of cholesterol is low.
  

1. Receptors will catch the LDL that carries cholesteryl ester in proteins.

2. The LDL is taken into the cell and the receptors are released and reused.

3. The protein inside of LDL is broken down into AA and the green part becomes cholesteryl oleate.

4. The green things turns into cholesterol and is used for membrane synthesis in the ER.

Atherosclerosis

blockage in the blod vessels due to increased plasma LDL, which leads to plaque, results in decreased blood flow.

treatment

• block de nova synthesis of cholesterol. T.ex inhibitors that blocks the production of mevalonate in stage 1 of production of cholesterol.

• better diet.

LDL (bad cholesterol) VS. HDL (good cholesterol)

LDL

• high level associated with atherosclerosis and coronary heart disease.

• may react with free radicals to form oxidized LDL, which triggers inflammation and increased risk of plaque formation.

• transported from the liver to the cells

HDL

• Reversed cholesterol transport, which removes the cholesterol to the liver.

• It inhibits LDL-oxidation.

Cholesterol as precursor

• bile salts

• Steroid hormones : testosterone, cortisol, Estradiol etc.

• Vitamin D

Caloric homeostasis

• Ability to maintain adequate, but not excessive, energy stores.

• consumed = expended + stored.

basal metabolic rate

• Happening constaintly

• The amount of energy needed to keep the body functioning at rest (50-70%)

Physical activity level

• Wall, stand etc (20-40%)

diet included thermogenesis

• thermic effect of food (5-15%)

Short term control of caloric homeostasis - CCK and GLP-1

the famous ozempic tries to mimmic GLP-1.

• these are small peptide hormones that signals satiety.

• gives appetite inhibiting signals, increasing satiety, and decreases food intake and body weight.

CCK

• induces secretion of pancreatic enzymes and bile salts.

GLP-1

• enhances insulin secretion and inhibits glucagon secretion.

Long term control of caloric homeostasis - Leptin and insulin

the cycle goes around like a “8”, if the process is disruped, it might cause diabetes.

Leptin

• control TAG storage

• supresses appetite by affecting the brain

• high leptin increases insulin sensitivity, decreses TAG synthesis.

Insulin

• controls both blood glucose level and affects the appetite.

• SOCS : blocking insulin signaling, and bnlocks degradation of receptors and IRS.

Diabetes

Type 1

• no insulin production

Type 2

• Produces insulin, but not accepted

• Obesity is a main risk factor, since it limits how much lipids can be hold in the alipocide, this causes lipids to enter other tissues, increasing chance of type 2 diabetes.
  

  treatment
  - Metformin
  - semaglutide
  - exercise bitch

Excess FAs will modifies the metabolism

• less glycogen synthesis

• less glucose uptake

• Less active insulin receptors —> decreased insulin signaling.

Insulin resistance and pancreatic failure

Insulin released by pancreas is regulated by the blood glucose conc (with ATP and ion channels)

• High [glucose] e.g high lipid levels stimulates insulin synthesis and secretion ( high ATP = changes potential = insulin release)

• The insulin are produced as pre-insulin, too much of those causes ER stress because the body can’t process that much insulin at the same time. ER tries to produce even more insulin.

• Too much insulin —> increased missfolding of proteins —> incresed chaperones —> increased breakdown of wrong proteins.

• Unfolded proteins —> UPR If ER stress can’t be fixed, them optosis (programmed cell death) will occur.

What is protein wasting? - starvation

When you are missing some of the essential AAs, which means that even though you consume proteins, a lot goes into waste.

• Often a consequence of starvation.

• when the glucose source is used, the body tries to find other sources, which creates ketone bodies.

• Once the lipid source is out in the adipocytes, proteins (heart, liver etc) will degrade —> death.