Chapter 29 - Lipid Synthesis

What is phosphatidate?

Acts as a backbone in many lipids

• formed via addition of two FA to glycerol 3-phosphate

What are phosphatidates used for?

Used either as a scaffold in either lipids or phospholipids

• for storage, it is linked to a third FA to form triacylglycerol

• catalyzed voa triacylglycerol synthetase complex bound to ER membrane

• occurs primarily in liver tissue to be stored in adipose tissue or transported to muscle for fuel

Triglycerides are primary storage form of energy in humans, 85%

What are phospholipids?

Important for cell membranes

• Three components

  • Backbone

  • 2 FA

  • Phosphorylated alcohol

also found in lung surfactants and some signaling molecules

What are glycerophospholipids?

The backbones of glycerol

• combo of DAG and alcohol

Needs to be activated to stick together to create the phospholipid

What happens when CDP-diacylglycerol is formed?

The DAG becomes activated, driven via the hydrolysis of PPi

• reactions with -OH

Then creates phospholipid and CMP

What happens when CDP-diacylglycerol reactions with inositol?

• It produces phosphatidylinositol

  • additional phosphorylations produced PIP2(3)

    • typically positioned in inner leaflet

What happens when CDP-diacylglycerol reactions with phosphatidylglycerol?

• It produces cardiolipin

What part of other glycerophospholipids are activated?

• Instead of DAG, the alcohol gets activated

  • examples:

    • phosphatidylethanolamine

    • phosphatidylcholine, component in mammalian membranes

What is a sphingolipid?

• A membrane lipid found in all eukaryotic cells

  • have a sphingosine backbone

What are the sphingolipids prescursors?

• Palmitate and serine

  • ceramide is the first s.l produced on addition of FA to sphingosine

    • other s.l are made by mods at terminal hydroxyl in ceramide

What are the head groups of sphingolipids?

Made via linking activated precursors to ceramide

• Sphingomyelin - important in myelin sheath, phosphorycholine head group

• Cerebroside - glucose head group

• Ganglioside - immune system binding sites, additon. sugars with sialic acids

What is cholesterol?

• Vital lipid in animal cells

  • essential in maintain membrane fluidity, and is a precursor for steroid hormones

Where is the primary site of cholestorol synthesis?

• In the liver

  • three stages:

    1. Production of activated five-carbon isoprene precursor, (cytoplasm

    2. Condenstation of six isopentenyl pyrophosphates to form squalene (30 carbons)

    3. Cyclization of squalene and formation of 27 carbon cholesterol molecule

What is the initial step and why is it important in cholesterol synthesis?

• Generation of HMG-CoA from acetyl CoA

• COMMITTED STEP, VERY IMPORTANT IN REGULATION

  • catalyzed by: HMG CoA reductase

What are the four mechanisms HMG-CoA reductase regulates?

• Transcriptional Control

• Translational control

• Control through protein stability

  • it changes the conformation of membrane domain, increasing degradation

• Control through phosphorylation state

  • AMPK phosphorylates to reduce activity when ATP level is low

What is SREBP?

• It increases the transcription of HMG-CoA reductase gene when bound to DNA

  • When inactive: is in ER membrane associate with SCAP, SCAP = the SREBP cleavage activating protein

  • When active: Activated when cholesterol falls and is escorted to golgi for cleavage

What is the fate of SREBP?

Depends on what SCAP associates with

• When cholest. low: SCAP binds to proteins to target complex to Golgi

• When cholest. present: SCAP binds to it, leading to Insig association and ER retention

What are the lipoproteins that transport cholesterol and triacylglycerols?

Sorted via density:

• VLDLs

• IDLs

• LDLs

• HDLs

What does VLDL do?

• Carry excess triacylglycerols, (TAGS) and cholesterol from liver

  • FA hydrolyzed and taken into target cells

What do IDLs do?

• Are remnants left over after unloading TAGs

  • can be taken up by liver or converted into LDLs

What are LDLs?

• Major carrier of cholesterol in cells

  • deliver to peripheral tissue

  • cell entry is through receptor mediated endocytosis

    1. LDL binds to cell surface LDL receptor

    2. receptor LDL complex is internalized via endocytosis

    3. LDL is hydrolyzed in lysosomes and receptor is recycled

What are HDLs?

• Transport cholesterol released from dying cells back to liver

  • reverse transport

What is familial hypercholesteremia?

• Condition in which LDL receptors are defective/absent

  • treatment via competitive inhibitors of HMG-CoA reductase