Lipid Metabolism III

Cholesterol

Has 27 carbon atoms.

Amphipathic with planar hydrophobic rings and polar OH group.
Chemically inert and stable.

Cholesterol Products

Bile acids.
Hormones
Lipoproteins (transport)
Coenzyme Q
Vit D
Membranes
Membrane targeting of proteins

Cholesterol Esters

TAG and cholesterol esters are completely hydrophobic and

stored in the ER.

Bile Acids

Made in liver from cholesterol.

Stored in gall bladder.
Emulsify lipids in small intestine.
Recycled from intestine to liver via enterohepatic circulation.
Fecal sterols are generated by intestinal bacteria from
cholesterol and bile acids and is a route of removal.
Conjugated bile acids contain modifications attached to the
carboxylate group.

Vit D

Can be obtained in the diet or made from cholesterol.

Need light dependent reaction to produce active vitamin D.

Endogenous Cholesterol Synthesis Pathway

Cholesterol is made in all tissues during well fed state.

3 Acetyl-CoA HMG-CoA Mevalonic acid Isoprenoid PP
Geranyl-PP Farnesyl PP Squalene Lanosterol
Cholesterol.

HMG CoA Reductase

The rate limiting step is catalyzed by HMG-CoA Reductase; 2

NADPH is used to reduce HMG-CoA to Mevalonic Acid.
Regulated by AMPK
Target of cholesterol lowering drugs (statins)

Cholesterol Transport Between Tissues

Cholesterol is transported by serum lipoproteins.

Lipoproteins are serum particles containing lipids and amorphous
proteins.
Apolipoproteins, cholesterol and phospholipids are on the surface
of the particles.
Triglycerides and cholesterol esters are in the interior of the
particles.
Lipoproteins are either produced in the intestine (chylomicrons)
or in the liver (VLDL) and then converted to other lipoproteins.

Serum Lipoproteins

Chylomicros made in intestine to transport lipids to liver and

non-hepatic tissues.
VLDL made in liver to transport every kind of lipids to nonhepatic tissues.
LDL derived from VLDL to transport cholesterol and cholesterol
esters to non-hepatic tissues.
HDL made from VLDL and LDL, transport cholesterol and
cholesterol esters back to liver.

Regulation of Cholesterol Synthesis

High insulin stimulates cholesterol synthesis.

AMPK phosphorylate/dephosphorylate HMG-CoA reductase.
Synthesis and degradation of HMG CoA reductase is regulated by
SREBP.
Liver cholesterol synthesis is regulated by uptake of lipoproteins.
Non-hepatic cholesterol synthesis is regulated by uptake of LDL.

SREBP

SREBP regulates Tx of LDL receptor and HMG CoA-reductase.

SCAP facilitates the transport of SREBP from ER to Golgi.
SREBP is cleaved by S1P and S2P in the Golgi to become
activated.
Activated SREBP enters nucleus and initiates Tx of LDL receptor
and HMG CoA reductase genes.

Cholesterol inhibits SCAP.