LIPIDS

Introduction• Fats are triacylglycerols containing saturated fatty acids

- solid at room temp - usually from animal source (however, coconut & palm oil are saturated).

• Oils are triacylglycerols containing mono- or polyunsaturated fatty acids

- liquid at room temp

- usually from plant sources (however, fish oils are polyunsaturated).

• Phospholipids are triacylglycerols that have had a FA replaced with a phosphate linked FA group.

• The major dietary sterol is cholesterol.

Health issues

• Excessive dietary fat intake is associated with obesity, diabetes, cancer, hypertension and atherosclerosis.

• Not more than 35% of energy intake should come from fat. Saturated fat should not make up more than 15% of the total fat intake.

• Omega-3 fatty acids (20 carbons) from fish may protect against atherosclerosis. American Heart association recommends 2-3 fish meals per weak. Fish oil supplements should be avoided because they may be contain concentrated toxins accumulated by the fish.  

FUNCTIONS OF LIPIDS: • Major components of cell membranes.

• Required to solubilise fat soluble vitamins

• Biosynthetic precursors (e.g. steroid hormones from cholesterol)

• Protection (e.g. kidneys are shielded with fat in fed state)

• Insulation

LIPID DIGESTION• Stomach - lingual lipase and gastric lipase attack

triacylglycerols and hydrolyse a limited number of FA.

• Small Intestine - acid chyme (stomach contents) stimulates mucosa cells to release hormone (choleocystokinin) which stimulates gall bladder and pancreas to release bile and digestive enzymes respectively (bile acids help emulsify fat droplets thus increasing their surface area).

• Other mucosa cells release secretin which causes pancreas to release bicarbonate rich fluid to neutralise chyme.

Enzymic digestion of lipids in small intestine

2-monoacylglycerol

• Enzymic digestion generates more polar products that form mixed micelles of free fatty acids, 2-monoacylglycerol, cholesterol & bile salts that are adsorbed (except bile salts which pass through to ileum – see later).

• Once adsorbed fatty acids and 2-monoacylglycerol are recombined to form triacylglycerol.

• Triacylglycerol + cholesterol + phospholipid + proteins form a lipoprotein complex called a chylomicron which transports the lipids in the circulation.

Lipid transport in the circulation

Lipids are insoluble in plasma. In order to be transported they are combined with specific proteins to form lipoproteins:

Non polar lipids in core (TAG and cholesterol esters)

Proteins (apoproteins)

Cholesterol

Apoproteins are only weakly associated with a particular lipoprotein and are easily transferred to another lipoprotein of a different class. Apoproteins have various functions including: • Structural role  • Binding sites for receptors  • Activators or co-enzymes for enzymes involved with lipid metabolism 

HO

HO

O

R

HOHO

O

R

HOHO

The five classes of lipoprotein(all contain characteristic amounts TAG, cholesterol, cholesterol esters,

phospholipids and apoproteins)

ClassDiameter

(nm) Source and functionMajor apoliproteins

Chylomicrons(CM)

500 Intestine. Transport of dietary TAG

A, B48, C(I,II,III) E

Very low density lipoproteins

(VLDL)

43 Liver. Transport of endogenously synthesised

TAG

B100, C(I,II,III) , E

Low density lipoproteins

(LDL)

22 Formed in circulation by partial breakdown of IDL.

Delivers cholesterol to peripheral tissues

B100

High density lipoproteins

(HDL)

8 Liver. Removes “used” cholesterol from tissues

and takes it to liver. Donates apolipoproteins to

CM and VLDL

A, C(I,II,III), D, EIncr

easi

ng

den

sity

• Assembled in intestinal mucosal cells.

• They enter the lymphatic system and enter the blood via the thoracic duct.

• They contain mostly TAG.

• Nascent chylomicrons contain apoprotein B48 but pick up others apoproteins from high density lipoproteins (HDL) once they enter the circulation.

Chylomicrons

Cholesterol ester

Apoprotein

TAG (86%)

Cholesterol

phospholipid

Function is to transport dietary TAG to the adipose tissues where it can be stored as fat or to muscles where the constituent fatty acids can be used for energy.

Lipoproteinlipase

Capillary wall(endothelial surface)

Tissues

HDL

CM

B48

CIIE

CM

B48

CIIE

CMR

B48

CIIE

CMR

B48

CIIE

Taken up byliver (via LDL receptors)

This animation shows how chylomicrons are metabolised once they enter the circulation from the lymphatic system

Chylomicrons• The nascent chylomicron enters the circulation carrying apoprotein B48 and a

large cargo of triacylglycerol (with a little cholesterol, cholesterol ester and

phospholipid). It receives apoproteins E and CII from high density lipoprotein

(HDL). The chylomicrons travel around the circulatory system until they associate

with lipoprotein lipase, an enzyme bound to the enodothelial surface. This

association is mediated through apoprotein CII. The lipoprotein lipase hydrolyses

the triacylglycerol to liberate free fatty acids which diffuse into the local tissues. As

triacylglycerol is lost, the chylomicron shrinks and forms a chylomicron remnant

(CMR). The released fatty acids can be reassembled into triaclyglycerol for storage

as fat or oxidised to produce ATP. The chylomicron remnant dissociates from the

lipoprotein lipase and returns apoprotein CII to HDL. The remnant is finally taken

up by the liver through receptor mediated endocytosis (liver receptors recognise

B48 and E). Dietary cholesterol delivered to the liver in CMR can be repackaged in

VLDLs and sent out to tissues or converted to bile salts. Dietary cholesterol inhibits

cholesterol synthesis by the liver.

Chylomicron summary

• Synthesised in intestine.

• Contain mostly dietary TAG (with a little cholesterol, cholesterol ester & phospholipid.

• Transport TAG to tissues and deliver remaining cholesterol & cholesterol ester to the liver.

Very low density lipoproteins (VLDL)• Synthesised in the liver. Contain mostly TAG but with a significant amount

of cholesterol and cholesterol ester.

• Nascent VLDL contains apoprotein B100 but pick up others from HDL in the circulation

Cholesterol

Cholesterol ester

TAG (55%)

Protein

phospholipid

Function is to transport endogenously synthesised TAG to the extra hepatic tissues where it can be stored as fat or to muscles where the constituent fatty acids can be used for energy. The cholesterol is delivered to extra hepatic tissues once VLDL has been metabolised to LDL.

LDL Lipoproteinlipase

Capillary wall(endothelial surface)

Tissues

This animation shows how VLDL are metabolised once they enter the circulation from the liver

VLDL

B100

E

CIIE

B100

Some LDL taken upby liver (LDL receptors)

Some LDL taken up byother tissues (LDL receptors).LDL delivers cholesterol and

TAG to the extra hepatic tissues.

Having lost TAG to tissues LDL contains a large proportion of cholesterol/cholesterol esters

VLDL synthesised in the liver with apoprotein B100. VLDL receives apoproteins

CII and E from HDL. Like chylomicrons, VLDLs travels around the circulatory

system until they associate with lipoprotein lipase, an enzyme bound to the

enodothelial surface. This association is mediated through apoprotein CII. The

lipoprotein lipase hydrolyses the triacylglycerol to liberate free fatty acids which

diffuse into the local tissues. As triacylglycerol is lost, the VLDL shrinks and

forms LDL. The released fatty acids can be reassembled into triaclyglycerol for

storage as fat or oxidised to produce ATP. The LDL return apoprotein CII and

E to HDL and are taken up by receptor mediated endocytosis by the extra

hepatic tissues (with some being taken back up by the liver). LDL having lost

most of their triacyglycerol are rich in cholesterol and cholesterol esters and

represent the route by which cholesterol is transported form the liver to the

tissues (although all tissues can make cholesterol to some extent).

VLDL

LDL membrane receptor

• Found in clathrin coated pits (endocytosis)

• After endocytosis the receptor is recycled whilst the LDL (or CMR) is degraded to releasing lipid cargo. Cholesterol uptake down regulates the cells own production of cholesterol and down regulates LDL receptor synthesis .

• Mutations in LDL receptors causes increased plasma LDL levels (i.e. increased cholesterol levels). This accelerates progress of atherosclerosis (Familial hyperlipedimias).

• The cholesterol in LDL is often called “bad cholesterol”.

Role of LDL in atherosclerosis• Damage to endothelium (hypertension, smoking etc).• LDLs penetrate vascular wall, deposit in the intima and with time are

damaged by oxidation.• Oxidised LDLs attract the attention of macrophages which ingest the LDL.• Macrophages become overloaded with lipid and become “foam” cells

which die and release pools of lipid in the vessel wall (plaques). • A complex processes mediated by cytokines and growth factors causes

smooth muscle cells to form a collagenous cap over the lipid (mature atherosclerotic plaque).

• Cap grows and can constrict the vessel (causing angina for example).• Macrophages can degrade the cap while T cells can inhibit collagen

synthesis – the cap can rupture to expose collagen and lipids• This leads to aggregation of platelets and blood clot formation.• If the coronary artery is blocked by a clot – heart attack. • Blocking of arteries in the brain causes stroke.• Antioxidants (vitamin E and C) may protect LDL from oxidation and so

protect against heart attack and stroke.

VLDL summary

• Synthesised in liver.• Contain mostly dietary TAG (with a little cholesterol,

cholesterol ester & phospholipid.• Converted to LDL which contain an increased

proportion of cholesterol & cholesterol ester (due to loss of TAG).

• Transport TAG and cholesterol from liver to tissues.• Cholesterol in LDL referred to as “bad cholesterol”

since LDLs are implicated in atherosclerosis

High density lipoprotiens• Act as a reservoir for apoproteins which can be donated or received from other

lipoproteins.• Also play a vital role in scavenging “used” cholesterol (reverse cholesterol transport):

HDL

Peripheral tissues

HDL

apoproteins

“used” cholesterol transferred to HDL and converted to cholesterol

ester

Liver

HDL receptor mediatedendocytosis by liver

Cholesterol can be converted to bile salts

for excretion orrepackaged in VLDL

for redistribution

VLDL

HDL

LDLLDL

LDLreceptor mediated

endocytosis

some cholesterol ester transferred to

circulating VLDL

High density lipoprotiens summary

• HDL carries “used” cholesterol (as CE) back to the liver. Also donate some CE to circulating VLDL for redistribution to tissues.

• HDL taken up by liver and degraded. The cholesterol is excreted as bile salts or repackaged in VLDL for distribution to tissues.

• Cholesterol synthesis in the liver is regulated by the cholesterol arriving through HDL (and dietary cholesterol returned by chylomicron remnants).

• Cholesterol (CE) in HDL is referred to as “good cholesterol”.

Bile salts• Excess cholesterol in liver is converted to bile salts. Bile salts are polar constitute

the major excretory pathway of cholesterol. • Stored in the gall bladder along with free cholesterol and phospholipids ready to be

secreted into the small intestine. Bile salts are strongly amphipathic and act as detergents to help break up (emulsify) dietary lipids.About 30g of bile salts and 2g of cholesterol are secreted by the bile duct every day. Cholesterol is present in bile at virtually the limit of its solubility and it can crystallise out to form gall stones)

• Almost all of this is actively reabsorbed so that only about 1-2g of bile salts and cholesterol are lost each day in the faeces. The reabsorbed bile salts and cholesterol are transported back to the liver bound to albumin and are recycled

• This cycle of secretion and reabsorption constitutes the enterohepatic circulation.• Fibre can bind bile salts and cholesterol and prevent its reabsorption. This is

considered to be one of the health benefits of fibre. Other treatments based on resins.

• Sitostanol ester (from plants) has a similar structure to cholesterol and stops cholesterol entering micellar phase and reduces its adsorbtion in to the blood stream (Benecol margarine).

O

OR

OH

Cholesterol

Cholesterolester

Esterification at the OHposition with a fatty acid

(catalysed by LCAT enzyme)

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