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Cholesterol anabolism and lipoproteins
Introduction, overview, and structure of cholesterol
Cholesterol has an important function on cellular structure and also in its function
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This increases its fluidity
because it's rich in phospholipids and sphingolipids with saturated fatty acids
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The absence of covalent bonding can be easily transferred in and out of the membrane
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The synthesis of cholesterol will be
regulated on a transitional and post transitional level
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The molecule has 27 carbons, 4 fused rings that contain 17
carbons
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It
will have 8 carbons as a side chain
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Almost all of
them are saturated except for the double bond found between carbon 5 and 6
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We can find cholesterol as free or as esterified cholesterol (CE)
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Synthesis of cholesterol
The synthesis of cholesterol requires a source of carbon atoms, a source of reducing power and
energy
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To start of the synthesis, acetyl-CoA will be transformed to Acetoacetyl-CoA
by acetoacetyl-CoA thiolase and later on to 3-hydroxy-3-methylglutaryl-CoA and finally to
mevalonate by the enzyme HMG-CoA reductase
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It uses 2 NADPH to do this reaction
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This two will generate geranyl pyrophosphate and isopentenyl
pyrophosphate will lead to farnesyl pyrophosphate
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Finally squalene will change to
squalene 2,3-oxide
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Regulation of cholesterol synthesis
At an organism level, the supply of cholesterol is either through diet or through de novo synthesis
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The
cell acquires cholesterol from both de novo synthesis and the external supply
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The intracellular (intramembrane) cholesterol
concentration is a key factor regulating both cellular cholesterol synthesis and the expression of
LDL receptors
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SREBPs are cleaved by a protease, releasing the active
transcription factors, which in turn translocate to the nucleus and activate all the genes in the

Cholesterol anabolism and lipoproteins
cholesterol synthetic pathway
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When cholesterol is depleted, the SCAP/SREBP complex dissociates from Insig-1 and travels to
the Golgi apparatus
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Primary bile acids are
synthesized in the liver Biosynthesis of the bile acids occurs in liver parenchymal cells, where
cholic and chenodeoxycholic acids are produced
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Liver X receptors participate in bile synthesis and secretion
Cholesterol is pumped into bile by ABCG5 and ABCG8 transport proteins, the expression of which
is regulated by the LXR
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Steroid hormones
Cholesterol is the precursor of all steroid hormones
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Conversion of cholesterol into steroid hormones
occurs in only three organs: the adrenal cortex, the testis in men, and the ovary in women
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They contain
triglycerides, cholesterol, phospholipids and proteins
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The hydrophobic cholesteryl esters and triglycerides reside in the core and amphipathic
phospholipids and free cholesterol along with proteins the outer layer
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The main
classes are chylomicrons, very low density lipoproteins (VLDL), remnant particles which are very
similar to the Intermediate density lipoproteins (IDL), low density lipoproteins (LDL) and the high
density lipoproteins (HDL)
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With a
decreasing triglyceride content the density increases and its size decreases
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The main
classes are:
Apolipoproteins A (AI & AII) – Present in HDL
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Apo AII is smaller than AI and is a cofactor for
the LCAT & CETP and it inhibits LPL
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Apo B48 is a
component of the chylomicrons synthesized in the enterocytes
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Apolipoproteins C (CI, CII & CIII) – they act as enzyme activators and inhibitors and they are
extensively exchanged between different lipoprotein classes
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It binds to the LDL receptor with a higher
affinity than B100 and it also binds the LDL-receptor-related protein LRP, stimulates the LPL, HTGL
& LCAT
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Cholesterol anabolism and lipoproteins
The cellular uptake of lipoproteins is mediated by lipoproteins binding to their receptors present on
cell membranes
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The receptor gene
is located on chromosome 19 and its expression is regulated by the intracellular cholesterol
concentration
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Two hydrolases, lipoprotein lipase (LPL) and hepatic trygliceride lipase (HTGL) remove
tryacylglycerols from lipoprotein particles
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LPL digests tryglicerides in chylomicrons and
VLDL , releasing fatty acids & glycerol to cells while HTGL acts on particles already digested by
LPL and facilitates the conversion of IDL into LDL

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