BCH 401 Note 2-1

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Lipid Biosynthesis

❖ Lipids are obtained from consuming food and absorbing them or


they are synthesized by an animal's liver through the process of
lipogenesis.

❖ The majority of lipids found in the human body from ingesting


food are triglycerides and cholesterol. Other types of lipids found
in the body are fatty acids and membrane lipids.

❖ Since lipids are hydrophobic molecules, they need to be


solubilized before their metabolism begin.
Digestion and Absorption of Dietary Lipids
❖Most lipids in the diets of mammals are triacylglycerols (TAG)
with smaller amounts of phospholipids and cholesterol.

❖The digestion of dietary lipids occurs mainly in the small


intestine, where suspended fat particles are coated with bile salts.

❖Bile salts are amphipathic cholesterol derivatives synthesized in


the liver, collected in the gall bladder, and secreted into the lumen
of the intestine.
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Digestion and Absorption of Dietary Lipids Contd.
❖Pancreatic lipase acts to degrade TAGs in the fat particles.

❖A small protein colipase helps bind the water-soluble lipase to the lipid substrates
and also activates lipase by holding it in a conformation with an open active site.

❖The initial products of fat hydrolysis are free fatty acids (primarily long-chain
molecules) and monoacylglycerols.

❖These products (molecules) are transported to the intestinal wall in bile-salt


micelles where they are absorbed by the cells lining the intestinal wall and the bile
salts are released.
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Digestion and Absorption of Dietary Lipids Contd.
❖The fate of dietary phospholipids is similar to that of TAGs.

❖Pancreatic phospholipases secreted into the intestine catalyse the


hydrolysis of phospholipids, which aggregate in micelles.

❖For example, phospholipase 2 catalyses the hydrolysis of


glycerophospholipids to form a lysophosphoglyceride and a fatty acid.

❖Lysophosphoglyceride are absorbed by the intestine and re-esterified


to glycerophospholipids in intestinal cells.
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Digestion and Absorption of Dietary Lipids Contd.

❖Most dietary cholesterol is unesterified.

❖Dietary cholesteryl esters are hydrolysed in the lumen of the


intestine by the action of an esterase.

❖Free cholesterol, which is insoluble in water, is solubilized by


bile-salt micelles for absorption.

❖Most cholesterol reacts with acyl CoA to form cholesteryl esters


in the intestinal cells. 5
Lipid Transport
❖TAG, cholesterol, and cholesteryl esters cannot be transported in blood
or lymph as free molecules because they are insoluble in water.

❖These lipids assemble with phospholipids and amphipathic lipid


binding proteins to form spherical macromolecular particles known as
lipoproteins.

❖A lipoprotein has a hydrophobic core containing TAGs and cholesteryl


esters and a hydrophilic surface consisting of a layer of amphipathic
molecules such as cholesterol, phospholipids, and proteins.
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Types of Lipoproteins

❖Chylomicrons

❖Very low density lipoproteins (VLDLs)

❖Low density lipoproteins (LDLs)

❖High density lipoproteins (HDLs)

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Size & Compositions of Lipoproteins

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Chylomicrons
❖Chylomicrons are formed in the endoplasmic reticulum in the
absorptive cells (enterocytes) of the small intestine.
❖They are the largest lipoproteins, consisting of approximately
98% lipid and 2% protein.
❖They are present in the blood only after a meal.
❖They deliver TAGs and cholesterol from the intestine via the
lymph and blood to tissues such as muscle (for oxidation) and
adipose tissue (for storage). 9
Very Low Density Lipoproteins
❖Very low density lipoproteins (VLDLs) consist of approximately
90% lipid and 10% protein; accounting for their very low density.

❖They are formed in the liver and carry lipids synthesized in the
liver, or needed by the liver, to other tissues such as adipose
tissue.

❖Lipases within capillaries of muscle and adipose tissue degrade


VLDLs and chylomicrons.
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Low Density Lipoproteins
❖Low density lipoproteins (LDLs) are enriched in cholesterol
and cholesteryl ester.
❖They deliver these lipids to peripheral tissues.
❖High levels of LDL (“bad” cholesterol) increase the chance of
developing atherosclerosis (the build up of lipid deposits in the
arteries which is associated with increased risk of coronary
heart disease that can lead to a heart attack).
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High Density Lipoproteins
❖High density lipoproteins (HDLs) are formed as protein-rich
particles in the liver.

❖They pick up cholesterol from peripheral tissues, chylomicrons,


and VLDL remnants, and convert it into cholesterol esters.

❖They transport cholesterol and cholesteryl esters back to the liver.

❖High levels of HDL (“good” cholesterol) are correlated with a


decrease in the risk of having a heart attack. 12
Serum Albumin
❖In addition to complex lipids such as cholesterol and TAGs, free
fatty acids are also transported in blood plasma.

❖Fatty acids bind to serum albumin, an abundant plasma protein.

❖They also bind many important drugs that are sparingly soluble in
water.

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Lipid Biosynthetic Pathways
❖In addition to dietary fats, storage lipids stored in the
adipose tissues are one of the main sources of energy for
living organisms.

❖Fatty acids, triacylglycerols, lipid membrane (including


cholesterol) can be synthesized by the organisms through
various pathways.
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Fatty Acid Biosynthesis
❖Fatty acids synthesis starts with acetyl-CoA and builds up by the
addition of two-carbon units.

❖The synthesis occurs in the cytoplasm of the cell, in contrast to the


degradation (oxidation), which occurs in the mitochondria.

❖Many of the enzymes for the fatty acid synthesis are organized into a
multienzyme complex called fatty acid synthase.

❖The major sites of fatty acid synthesis are adipose tissue and the liver.
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Fatty Acid Biosynthesis Contd.

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Fatty Acid Biosynthesis Contd.

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Fatty Acid Biosynthesis Contd.

❖Some sphingolipids contain C22 and C24 fatty acyl groups. These and other
long chain fatty acids are generated by enzymes known as elongases,
which extend the C16 fatty acid produced by fatty acid synthase.
❖Elongation can occur in either the endoplasmic reticulum or mitochondria.
The endoplasmic reticulum reactions use malonyl-CoA as the acetyl-group
donor and are chemically similar to those of fatty acid synthase.
❖In the mitochondria, fatty acids are elongated by reactions that more
closely resemble the reversal of β oxidation but use NADPH.
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Fatty Acid Biosynthesis Contd.

❖ Desaturases introduce double bonds into saturated fatty acids. These reactions take
place in the endoplasmic reticulum, catalyzed by membrane-bound enzymes.
❖ The electrons removed in the dehydrogenation of the fatty acid are eventually
transferred to molecular oxygen to produce H2O.
❖ The most common unsaturated fatty acids in animals are palmitoleate (a C16
molecule) and oleate (a C18 fatty acid), both with one cis double bond at the 9,10
position.
❖ Elongation can follow desaturation (and vice versa), so animals can synthesize a
variety of fatty acids with different chain lengths and degrees of unsaturation.

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Fatty Acid Biosynthesis Contd.
❖ However, mammals cannot introduce double bonds at positions beyond C9 and therefore
cannot synthesize fatty acids such as linoleate and linolenate. These molecules are
precursors of the C20 fatty acid arachidonate and other lipids with specialized biological
activities.
❖ Mammals must therefore obtain linoleate and linolenate from their diet. These essential
fatty acids are abundant in fish and plant oils.
❖ Unsaturated fatty acids with a double bond three carbons from the end, omega-3 fatty
acids, may have health benefits.
❖ A deficiency of essential fatty acids resulting from a very-low-fat diet may elicit symptoms
such as slow growth and poor wound healing.
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Triglyceride Biosynthesis
❖The phosphatidic acid is a precursor for triglyceride
biosynthesis.

❖Phosphatidic acid phosphatase catalyzes the conversion of


phosphatidic acid to diacylglyceride, which will be
converted to tryacylglyeride by acyltransferase.

❖Tryglyceride biosynthesis occurs in the cytosol.


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Triglyceride Biosynthesis Contd.

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Membrane Lipid Biosynthesis
❖There are two major classes of membrane lipids: glycerophospholipids and
sphingolipids.

❖Although many different membrane lipids are synthesized in our body, pathways
share the same pattern.

❖The first step is synthesizing the backbone (glycerol or sphingosine), the second
step is addition of fatty acids to the back bone to make phosphatidic acid.

❖Phosphatidic acid is further modified with the attachment of different hydrophilic


head groups to the back bone.

❖Membrane lipid biosynthesis occurs in the endoplasmic reticulum membrane. 23


Cholesterol Biosynthesis
❖Cholesterol can be made from acetyl-CoA through a multiple-step
pathway known as Isoprenoid Pathway.

❖Cholesterols are essential because they can be modified to form


different hormones in the body such as progesterone.

❖ 70% of Cholesterol biosynthesis occurs in the cytosol of liver


cells.

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Cholesterol Biosynthesis Contd.

Note: HMG-CoA means 3-hydroxy-3- methyl-glutaryl-CoA 25

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