Chem 674

Sources of Lipids

• Biosynthesis from acetyl-CoA• Dietary intake• Limited ability to synthesize

unsaturated fatty acids (humans)

You are what you eat

Lipids• like CHO, lipids are composed of carbon, hydrogen and oxygen

• unlike, CHO they do not contain multiple hydroxyl groups for hydrogen bonding, and therefore are insoluble in water

• Lipids include a large variety of molecules:- fatty acids- triglycerides- waxes- eicosanoids- steroids- fat soluble vitamins

Recommended Dietary Needs

• insoluble in water

• wide range of functions: insulate and protect internal organs, signaling molecules, energy

• most efficient form in which energy is stored in the body

• fats in animals absorb and sequester nonpolar contaminants, such as DDT, PCBs, organomercury

•excess glucose, lipids and proteins are stored in adipose cells

General info on Lipids…

Lipids: diverse class of molecules

1) Energy and storage – fatty acids, triacylglycerides, waxes

2) Membrane structure – phospholipids, glycolypids, sterols

3) Signaling, cofactors and pigments – Eicosanoids, sterols, fat soluble vitamins

Energy & storage Lipids

• Fatty Acids

• Triacylgerols

• Waxes

Triglycerides• The lower melting points of triglycerides rich in

unsaturated fatty acids are related to differences in their three-dimensional shape.– Hydrocarbon chains of saturated fatty acids can lie

parallel with strong London dispersion forces between their chains; they pack into well-ordered forms and melt above room temperature

– Because of the cis configuration of the double bonds in unsaturated fatty acids, their hydrocarbon chains have a less ordered structure and London dispersion forces between them are weaker; these triglycerides have melting points below room temperature.

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Triacylglycerols: stored fat

• Insulation - seals, walruses, penguins• Energy – Hibernation

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Properties of Triglycerides• Highly reduced hydrocarbons• Insoluble in water• Segregated into lipid droplets• Good storage properties make them difficult as fuels

– Must be emulsified before digestion– Must have special transport in the blood– The relative stability of the C-C bond must be

overcome• 3 sources: diet, adipose tissue, and synthesis from

carbohydrates

Emulsification

• Fats are not water soluble

• Made soluble by bile salts (amphipathic) that are made in the liver and stored in the gall bladder

• Converted to mixed micelles of bile salts and triacylglycerols

Bile Salts• Bile salts, the oxidation products of cholesterol.

– synthesized in the liver, stored in the gallbladder, and secreted into the intestine where they emulsify dietary fats and aid in their absorption and digestion

Fat digestion and Absorption

https://www.youtube.com/watch?v=O1XToe78zxs

Packaging for transport• Converts triacylglycerols to monoacylglycerols and

diacylglycerols, fatty acids, and glycerol

• Diffuse into epithelial cells lining intestine

• Converted back to triacylglycerols and packaged with cholesterol and proteins into chylomicrons

• Contain apolipoprotein C-II for recognition

• Travel into lymphatics and then blood to target

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What does a chylomicron look like?

Lipoprotein particles classified by density: Chylomicrons / VLDL / LDL / IDL/ HDL

Proteins recognized by cell surface receptors

ApoCII binds LPL in adipose tissue and skeletal muscle

lipid-binding proteins in the blood

Chylomicrons• assembled in intestinal mucosa, carry exogenous fats and cholesterol via

lymph system to large body veins

• Adhere to inner surface of capillaries in myocytes and adipocytes

• Fats contained within (not cholesterol) are hydrolyzed by lipoprotein lipase, freeing fatty acids and monoacylglycerols

• The remaining structure is called a chylomicron remnant, which contains cholesterol

• Remnant reenters circulation system where it is taken up by liver

• Thus, chylomicrons deliver dietary fats to muscle and adipose tissue and cholesterol to liver.

Lipoproteins• Cholesterol, along with fats, are transported by

lipoproteins

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Chylomicron LDL

Lipoproteins

Lipoproteins• Cholesterol, along with fats, are transported by

lipoproteins

Apoproteins or apolipoproteins• protein components of lipoproteins • proteins, though water soluble, have a hydrophobic and a

hydrophilic character that is apparent in their alpha helices• Their alpha helical regions are stabilized upon incorporation

into lipoproteins • There are 10 apoproteins common in humans

VLDL, IDL, and LDL are interrelated• VLDL- Excess FA and glucose is converted into

hepatic TG and transported as VLDL to muscle and adipose

-like chylomicrons, VLDL are degraded by LPL• IDL and LDL appear in the circulation as VLDL

remnants. – After unloading TG, VLDL is converted to LDL by removal of all

proteins except apo B-100 and esterification of most of the cholesterol by lecithin-cholesterol acyl transferase (LCAT) associated with HDLs.

HDL Transports Cholesterol from Tissues to the Liver

• removes cholesterol from tissues and transports it to the liver.

• HDL is created mostly from components from other degraded lipoproteins.

• HDL converts cholesterol to cholesteryl esters by LCAT, an enzyme activated by apoA-I in HDL.

• HDL appears to get cholesterol to the liver 1) by transfer of the cholesteryl ester to VLDL which

after degradation to IDL and LDL is taken to the liver 2) by direct interactions between HDL and the liver via a specific HDL receptor. • The liver disposes of cholesterol as bile acids. • also called "good cholesterol" because it is associated with

lowering cholesterol levels.

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the real pictureSize1000nm70nm20nm10nm

Cholesterol• Cholesterol is the most abundant steroid in the

human body, and also the most important.– It is a component in plasma membranes in all animal

cells.– It is the precursor of all steroid hormones and bile

acids.

Cholesterol uptake• Cholesterol makes it to

animal cell membranes by either external transfer, or by cellular synthesis

• Exogenous cholesterol reaches cells from LDL

• LDL binds to LDL receptors, which are transmembrane proteins that bind both ApoB-100 and apoE

• The receptors form clusters of “coated pits”

Receptor mediated endocytosis

• Clathrin, the scaffolding protein of the coated vesicles, forms the backing of the coated pits.

• The pits invaginate into the plasma membrane forming coated vesicles that fuse with the lysosomes

• The lysosomes hydrolyze the cholesteryl esters, yielding free cholesterol

• This cholesterol can be incorporated into cell membranes or reesterified for storage

• Interestingly, high intracellular cholesterol suppresses synthesis of LDL receptor and biosynthesis of cholesterol

Steroids

• Steroids: a group of plant and animal lipids that have this tetracyclic ring structure.

Steroids

• cholesterol, bile acids, vitamin D, and many hormones

• Oxidized sterols

• Lipid soluble and enter cells

• Bind nuclear receptors and alter gene expression and metabolism

Fat Metabolism

I’m not fat, I’ve just got a lot of potential energy!

Role of Hormones

• Can mobilize fats from adipose

• Release as Fatty acids

• Epinephrine and glucagon secreted in response to low glucose activates the of release cAMP

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Mobilization of Stored Triglycerides

• Epinephrine and glucagon initiate lipolysis

• Fat droplets in adipose coated with perilipins – proteins that restrict access to lipid droplets

• cAMP-dependent PKA phosphorylates perilipin, causing activation of lipase

• What is the fate of the glycerol backbone?

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Glycerol Oxidation

95% of the energy in a fatty acid is derived from the oxidation of acetyl-CoA

5% from glycerol

Animation of Process

• http://www.wiley.com/legacy/college/boyer/0470003790/animations/fatty_acid_metabolism/fatty_acid_metabolism.htm

Fatty Acids and Energy• Fatty acids in triglycerides are the principal

storage form of energy for most organisms.– Hydrocarbon chains are a highly reduced form of

carbon.– The energy yield per gram of fatty acid oxidized is

greater than that per gram of carbohydrate oxidized.

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Storage vs. Structural lipids in membranes

More on Lipids……

• fats insulate and protect internal organs• most efficient form in which energy is stored in the body

-9 kcal/ gram as opposed to 4

• fats in animals absorb and sequester nonpolar contaminants, such as DDT, PCBs, organomercury

• excess glucose, lipids and proteins are stored in adipose cells