• Triacylglycerides
• Membrane Lipids
• Cholesterol
  

• fromed from glycerol-3-phosphate
• precursor to triacylglycerols and phospholipids
  

• Occurs in the liver
  
• Requires activated FA (fatty acyl CoA)
• Triacylglycerol syntahse complex (ER membrane)
  

• Formed from Diacylglycerol - DAG (from phosphotidate) and an alchohol
  
• Either DAG or alcohol has to be activated for synthsis to occur
  

• Phosphotidate reacts with CTP (nucleotide) to form CDP-diacylglycerol

• Ethanoloamine or choline is phosphorylated by ATP
  
• Then reacts with CTP to form CDP-ethanolamine or CDP-choline
  

• very important lipid - most common phospholipid, normally formed through activation of choline
  
• If limited choline, can also be formed from phosphatidylethanolamine in liver.
  

• sphingoloids have sphingosine backbone instead of glycerol backbone.
  
• Made from ceramide precursor
  

• Sphingomycin
• Cerebroside
• Gangliosides
  

• Essential to membrane fluidity
  
• Precursor of steroid hormones: Progesterone, Testerone
  

• All C atoms come from acetyl CoA
• Four stages: -
  

1. Synthesis of mevalonate (cytoplasm)
2. Synthesis of isopentenyl pyrophosphate - IPP (cytoplasm)
3. Formation of squalene (ER lumen)
4. Cyclization of squalene (ER lumen)
   

Synthesis of mevalonate (cytoplasm)

• Formation of HMG-CoA
• Reduction of HMG-CoA to Mevalonate
  

                *Committed step in chlosesterol synthesis

                *Catalyzed by HMG-CoA reductase.

Synthesis of Isopentenyl pyrophosphate - IPP (cytoplasm)

• 6C molecule (Mevalonate) → 5C molecule (IPP)
• Isomerization of Isopentenyl pyrophosphate
  

*Forms other activated iosprene necessary for next step in synthesis
*Catalyzed by isopentenyl pyrophosphate (IPP) isomerase

Formation of squalene → linear 30C molecule

• Dimethyallyl phyrophosphate (C5) + IPP(C5) → geranyl phyrophosphate (C10) + IPP (C5) → Feranyl pyrophosphate (C15)
• Condensation reactions catalyzed by prenyl transferase
• Two molecules of feranyl pyrophosphate combine to form squalene:

               *Both pyrophosphate groups eliminated
              *Catalyzed by squalene synthase

Cyclization of squalene (ER lumen)

• Activation of squalene to squalene epoxide

*Requires NADPH and  O₂
*Catalyzed by squalene monooxygenase

• Cyclization catalyzed by a cylcase forms lanosterol (C30) → an intermediate
• Multiple steps remove 3 C to form cholesterol
  

• key regulatory enzyme: HMG-CoA reductase
  
• Catalyzes the formation of mevalonate from HMG-CoA
• Transcription controlled by sterol regulatory element binding protein (SREBP)
• Translation controlled by inhibitors
• Proteolytic degradation
  
• Phosphorylation
  

Embedded in the ER; binds together w/ SCAP

• If sterol (binds SCAP, presevents release of SREBP) is inhibited, SREBP-SCAP complex can migrate to the Golgi complex
  
• Cleavage by 1st protease
• Cleavage by 2nd protease → released domain of SREBP migrates to nucleus
• Transcription of target genes is activated  → turning on cholesterol synthesis when there are low levels of cholesterol in the cell.
  

• Translation of HMG-CoA reductase
  

*Inhibited by dietary cholesterol and mevalonate derivation 

• HMG-CoA reductase has two domains
  

               *Cytoplasmic domain - active site
               *Membrane domain (ER membrane)

• Membrane domain is more susceptible to proteolysis with increasing concentrations of sterol
  

              *Structural change

• Phosphorylation of HMG-CoA reductase inactivates the enzyme
  
• AMP-activated protein kinase → Low ATP levels inhibits cholesterol synthesis
  
• Insulin promotes dephosphrorylation
  
• Glucagon promotes phosphorylation (turning it off!)

Phosphorylated = inactivated

• Limited amount used in membranes of liver cells
  
• Rest is exported from liver as:

          *Biliary cholesterol
          *Bile acids: aid in lipid digestion
          *Cholesteryl esters: formed by acyl CoA-cholesterol acyl 

            transferase (ACAT)

• Used in membrane synthesis, hormone productin, vitamin D synthesis.
  

• Cholesterol and triacylglycerols are transported by plasma lipoproteins
  
• Lipoproteins:

            *Core of hydrophobic lipids
            *Shell of more polar lipids and proteins

• transport cholesterol to peripheral tissues →primary way
  
• also regulate synthesis at periphral tissues
• Sometimes called 'bad cholesterol'

          *only 'bad' in excess
          *contributes to formation of atherosclerotic plaques on arterial

            walls.

• Normally removed from the body by receptor-mediated endocytosis
  

• Side-chain cleavage and oxidation of cholesterol
  
• Bind to proteins that are transcription factors
• All steroid hormones come from cholesterol
  

• Act similar to steroid hormone
• Important for bones!