lipid metabolism. i.lipid digestion, absorption, and transport triglycerides ~ 90% of dietary lipids...

LIPID METABOLISM

I. Lipid Digestion, Absorption, and Transport

Triglycerides ~ 90% of dietary lipids Metabolic NRG storage

Oxidized to CO2 and H2O

Triglyerides, cont…

oxidation state than glucose metabolism of fats yields

~9 kcal/gram vs ~4 kcal/gm Carbohydrates, proteins

Triglyceride Storage, cont…

Stored in anhydrous state Non-polar Provide ~ 6 times energy of

hydrated glycogen

Triglyceride storage, cont…

Stored in large quantities in cells Non-reactive with other cell components Segregated into lipid droplets Do not affect osmolarity of cytosol

Triglycerides, cont…

To be used as fuel: insoluble in H2O Must emulsify before lipid digestion in

intestine Must be “carried” in blood (proteins)

Triglycerides, cont…

Sources of fat Three cellular sources

Fat in diet Fat stored in cells Fat synthesized in one organ and

transported to another

Triglycerides, cont…

Fats obtained vary by organism Vertebrates

Fat in diet Fat in adipose tissue Convert excess carbohydrate to fat

in liver for export

Triglycerides, cont…

Humans Industrialized countries:

~ 40% of daily calorie consumption is fat

Should be < 30%! Atkins kills…

Humans, Triglycerides, cont…

Used for > half the energy in: Liver Heart Resting skeletal muscle

Humans, Triglycerides, cont…

Hibernating animals and migrating birds

sole source of NRG Higher plants:

Do not depend on fats for energy Germinating seeds

Lipid digestion, cont…

Digestion Triglyceride digestion

takes place at lipid-water interfaces Rate is based on surface area at

interfaces Peristalsis Emulsification by bile

Lipid digestion, cont…

Bile Synthesized from cholesterol,

biliverdin By liver Stored in gallbladder Released after ingestion of fat

Lipid digestion, Bile, cont…

Acts as digestive detergent Converts dietary fats into mixed

micelles Micelles contain bile salts and

triglycerides

Lipid digestion, cont…

Role of lipase Pancreatic lipase:

catalyzes hydrolysis of triglycerides At 1 and 3 positions sequentially Forms 1,2-diglycerol 2-glycerol Soap

Role of lipase, Lipid digestion, cont…

Phospholipase A: Pancreatic enzyme Degrades phospholipids Hydrolysis at C(2)

Absorption of Lipids

Absorption Molecules diffuse into cells of

intestine Facilitated by bile salts

Micelles transport non-polar lipids across aqueous boundary layer

Absorption, cont…

Bile salts essential Fatty Acids Fat soluble vitamins

A,D,E & K Biliary disease interferes

Lipid Uptake in Vertebrates

Role of Lipase, cont…

Reconversion: in mucosa cells Lipid digestive products

triglycerides Packaged into Chylomicrons

Lipoprotein aggregates Triglycerides, cholesterol, protein

Chylomicron

Aggregate of triglycerides, cholesterol, and proteins

Reconversion, Role of Lipase, cont…

Released into bloodstream: Via lymphatic system Lacteals

Triglycerides synthesized in liver Packaged in VLDL Directly released into blood

Role of lipase, cont…

Transport APOLIPOPROTEINS: lipid-binding

blood proteins Transport between organs

Form classes based on density

Role of lipase, cont…

Proteins on outside of Chylomicron Are apoproteins Act as cell surface receptors for

recognition (apo C-II)

Lipid Uptake in Vertebrates

Transport, Role Chylomicrons, cont…

Chylomicrons and VLDL: Move triglycerides, cholesterol To Skeletal muscle & adipose LIPOPROTEIN LIPASE

an extracellular enzyme Activated by apo C II Hydrolyzes triglycerides

Chylomicron

Carry triglycerides, cholesterol to tissues via lymphatic system (lacteals)

Transport, Role of lipase, cont…

Deletes lipoprotein from triglyceride Forms IDL Then LDL

LDL: (130-159 mg/dl) removed from plasma at liver, adrenals, adipose

HDL: (above 35 mg/dl) moves cholesterol from tissues Sends to liver for excretion in bile salts

Ratio LDL:HDL = 2:1

Lipid Metabolism, cont…

Uptake by cells FA taken in by:

muscle: oxidized for NRG adipose: stored as triglyceride

Lipid Uptake in Vertebrates

Transport, Role of lipase, cont…

Glycerol Transported to liver or kidney Converted to dihydroxyacetone

phosphate And then???

Pathway to Glycolosis

Conversion of glycerol to dihydroxyacetone phosphate

Transport, Role of lipase, cont…

Remnants of Chylomicrons triglycerides; cholesterol and

apoproteins (apo E, apo B-48) To liver

Uptake by endocytosis Triggered by apolipoproteins

Uptake in Liver via Endocytosis

Chylomicron Remnants, cont…

Triglycerides Oxidized for energy or Converted to ketone bodies

Excess fatty acid Convert to triglycerides Pack into VLDL To adipose for storage

Lipid Uptake in Vertebrates

Mobilization of Stored Fats

Mobilization of stored triglycerides Triggered by hormones

Stimulus is in blood glucose Hormones:

Epinephrine Glucagon

Mobilization of Stored Fats, Hormone Action, cont…

Activate adenylate cyclase in adipocyte plasma membrane

Increases cAMP Activates protein kinase Activates triglycerol lipase Catalyzes hydrolysis of ester bonds in

triglycerides

Mobilization of Stored Fats

Action of second messenger hormones triggers mobilization of stored triglycerides

Role of lipase, cont…

Free fatty acid released into bloodstream

Binds to serum albumin Carried to tissues

Released to diffuse into cells

Role of lipase, cont…

NOTE: Glycerol glycerol-3-phosphate dihydroxyacetone phosphate glycolysis

II. Fatty Acid Oxidation

FA activation: Free FA cannot enter Mitochondria Occurs in cytosol

Acyl-CoA synthetases (thiokinases) 3 isozymes mitochondrial membrane

FA activation, cont...

FA + CoA + ATP fatty acyl-CoA + AMP + PPi

different acyl-CoA’s work on different FA

Fatty acyl-CoA: high energy compound

Fatty acid oxidation, cont…

Transport across mitochondrial membrane: Formation of fatty acyl-carnitine

Carnitine acyl transferase I Outer face of inner membrane Fatty acyl from CoA carnitine CoA released cytoplasm

Transport across mitochondrial membrane, cont…

Acyl-carnitine/carnitine transporter Carrier Fatty acyl-carnitine matrix carnitine to inter-membrane space Facilitated diffusion

F.A. Entry into Mitochondria

Fatty acid oxidation, cont…

Transfer of acyl from Carnitine to intra-mitochondrial membrane

Carnitine acyltransferase II Inner face of inner membrane Regenerates fatty acyl-CoA Frees carnitine returns to cytosol

Carnitine Acyltransferase II, cont…

Two separate pools of CoA (ATP, NAD+)

Cytoplasm: makes FA Mitochondria: oxidative degradation

Pyruvate FA AA

ß-oxidation

ß-oxidation: FA dismembered to fatty acyl-CoA Mitochondrial oxidation of FA

Stage One: ß-oxidation Remove 2-C chunks as acetyl-CoA Begins at carboxyl end of fatty acid chain

ß-Oxidation

Fatty acids are dismembered into Acetyl-CoA subunits

Each acetyl Co-A sends 4 H to NAD, FAD

Mitochondrial oxidation, cont…

For example, 16C palmitic acid 8 acetyl CoA

Stage Two: oxidation of acetyl-CoA CO2

Stage Three:

oxidative phosphorylation

ATP (+H2O)

ß oxidation, cont…

ß oxidation: 4 reactions Formation of a trans – , ß double

bond Between C-2 () and C-3 (ß) Yields: Trans-∆2-enoyl-CoA Acyl-CoA dehydrogenase FAD 2 ATP Similar to succinate dehydration

ß-Oxidation

First: formation of double bond

Second: hydration of double bond

Third: dehydrogenation

Fourth: cleavage to Acetyl Co-A

ß-oxidation, cont…

Hydration of the double bond By enoyl-CoA hydrase Forms 3-L-hydroxyacyl-CoA Similar to fumarase reaction

ß-oxidation, cont…

Dehydrogenation By ß-hydroxyacyl-CoA

dehydrogenase To ß-ketoacyl-CoA NAD 3 ATP Similar to malate dehydrogenase

reaction

ß-oxidation, cont…

C -Cß cleavage (thiolysis) Catalyzed by ß-ketoacyl-CoA thiolase

(thiolase) Produces:

acetyl-CoA fatty acyl-CoA (2 carbons short)

ß oxidation: Enzymes in Mitochondrial membranes

3 kinds of acyl-CoA dehydrogenase Specify short, medium, long chain fatty

acid Medium-chain acyl-CoA dehydrogenase

(MCAD) Deficient in ~10% of SIDS babies More common than PKU

Sites of Mitochondrial Enzymes

ß-oxidation, cont…

Fatty acid oxidation is highly exergonic Each round of ß-oxidation

1 NADH 1 FADH2

1 acetyl-CoA

ß-oxidation, Energy Payoff

Acetyl-CoA citric acid cycle Example: PALMITOYL-CoA (16C)

7 rounds of ß -oxidation 7 NADH 7 FADH2

8 acetyl CoA So, 7 + 24 NADH = 31 x 3 = 93 ATP

7 + 8 FADH2 = 15 x 2 = 30 ATP + 8 GTP 131 hi-energy molecules

for fatty acyl CoA - 2 ATP

129 total

ß-oxidation, cont…

READ IN TEXT: Oxidation of unsaturated fatty acid:

2 additional reactions Oxidation of odd-chain fatty acid:

3 additional reactions

III. Ketone Bodies

Acetyl-CoA from ß-oxidation Enters citric acid cycle Converted to KETONE BODIES

Water-soluble “equivalent” of FA

Ketone bodies, cont…

Ketogenesis Occurs in liver:

acetyl CoA ketone bodies Primary ketone bodies

Acetoacetate - out of liver D-ß-hydroxybutyrate - out of liver Acetone - exhaled

Ketone Body Formation

Ketone bodies, cont…

Function: fuel for peripheral tissues Heart, skeletal muscle Brain

Normal fuel is glucose In starvation: ketone bodies

Enzyme production adapts over time >40 days, provide 70% energy

Ketone bodies, cont…

Production and transportation Determined by availability of

oxaloacetate Combine with acetyl group enter TCA cycle

Ketone bodies, cont…

In starvation Oxaloacetate pulled from citric

acid cycle Used in gluconeogenesis

[oxaloacetate] decreases therefore little kreb’s cycle Production of ketone bodies is

favored

Production and transportation, cont…

Overproduction: starvation, diabetes Moved from liver to other tissues

Allows fatty acid oxidation in liver In tissues:

ketone bodies converted back to acetyl-CoA

Production and transportation, cont…

Formation of ketone bodies from acetyl-CoA occurs in the mitochondrial matrix

thiolase 2 Acetyl-CoA acetoacetyl-CoA Acetoacetyl-CoA + acetyl-CoA

ß -hydroxy- ß -methylglutaryl-CoA HMG-CoA free acetoacetate + acetyl-CoA

Production and transportation, cont…

Acetoacetate D- ß -hydroxybutyrate dehydrogenase

D-ß-hydroxybutyrate Acetoacetate decarboxylase

Acetone High in uncontrolled diabetes

Production and transportation, cont…

Ketosis Pathological Acetoacetate produced too fast

for elimination Breath smells like acetone Blood pH decreases acidosis

Lipid Biosynthesis

“Reverse” of lipid catabolism Know differences

Where in the cell does each occur? What are the e- transport

molecules? What are the acyl group carriers? Where does acetyl Co-A “fit into”

each set of reactions?

Pathway Differences

Fatty Acid Biosynthesis

Read in Text For major

steps, know Type of

reaction Enzyme Product

Cholesterol Biosynthesis

Read in Text Know

Draw steps Intermediate

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