Today’s topics:

Fatty Acid Metabolism Cholesterol Biosynthesis Catabolic - Lipases and b-oxidation

Triglyceride (Fat)

OCH2-O - C-R | OCH –O - C-R | OCH2-O - C-R

Glycerol + 3 Fatty Acids

insulin to blood

glucagon

Lipase

Both Liver & Muscle can oxidize Fatty Acids.Fatty Acids transported by Serum Albumin in blood

Brain cells can’t metabolize Fatty Acids (can’t enter)

[Glu]blood

Insulin

Meal

Fatty Acid Synthesis Fed State

Insulin (& citrate) stimulate AcetylCoA carboxylaseGlucagon/epinephrine inhibit

glucagonGlucagon stimulates Lipase activity in adipose.Fatty Acids released to blood to be used as fuel by other cells.

Fasting State

Glucagon effect on adipose

I

II

III

HSA with 8 myristate (green) – Trp214 (purple)

Serum Albumin transports FAs in blood

Ibuprofen – Drug site II in Domain IIIA of HSA with secondary site in domain II

I

II

III

W214

b – Oxidation (what?)

Fatty Acid + ATP + CoASH → (Fatty Acyl CoA)n + AMP + PPi

activation stepPPi 2Pi series coupling favors (fatty acyl CoA)n over fatty acid

(Fatty Acyl CoA)n + NAD+/ FAD + CoASH b-oxidation ‘spiral’

(Fatty Acyl CoA)(n-2) + NADH/FADH2 + Acetyl CoA

Palmitate (C16) + 7FAD + 7NAD+ + ATP + 8 CoASH Net reaction

8Acetyl CoA + 7FADH2 + 7NADH, H+ + AMP + 2Pi

H H H H O- C – C – C – Cb – Ca – C – SCoA

H H O- C – C – C – Cb – Ca – C – SCoA

OH H H H O- C – C – C – Cb – Ca – C – SCoA

O H H O- C – C – C – Cb – Ca – C – SCoA

O O- C – C – C – Cb – SCoA + CH3 – C – SCoA

H2O

CoASH

FAD

FADH2

dehydrogenase

NAD+

NADH,H+

dehydrogenase

Glucose

AcetylCoA

Pyruvate

NADH/FADH2

KrebsCycle

C6

C4

C5

C4

ATP

Glycolysis

Bridging Rx.

Oxidative Phosphorylation

ADP O2

NAD+/FAD

Fatty acid catabolism

AcetoacetylCoA

Fatty acids

Fat (triglycerides)

b-oxidation

Lipase

Why? Utilize energy storesWhere? Liver & Muscle (not in brain)When? Fasting State

[Glu]blood

Meal

Insulin

Glucagon

Fed

Fast early

late fast

Glycogen gone

6-12 hrs1-2 hrs

3 daysLong Term Fast

Liver Gluconeogenesis provides glucose to blood/brain.

Fatty Acid Metabolism

High Fat use [AcetylCoA]

Glucose

AcetylCoA

Pyruvate

NADH/FADH2

KrebsCycle

C6

C4

C5

C4

ATP

Bridging Rx.

Oxidative Phosphorylation

ADP O2

NAD+/FAD

Fat Metabolism - Liver

AcetoacetylCoA

Fatty acids

Fat (triglycerides)

b-oxidationKetone Bodiesacetoacetate b-hydroxybutyrate acetone

Ketone Body Formation

To blood

Gluconeogenesis

X

X

O ||CH3 - C - CH3

OH |CH3 - CH - CH2 - COO-

acetone O ||CH3 - C - CH2 - COO-

acetoacetate

b - hydroxy butyrateKetone Bodies

to blood

Ketone Body Formation

What: acetylCoA ketone bodiesWhy: provide blood with fuel alternate to glucose to minimize protein breakdown Where: Liver

When: Fasting State - Late & Long-term simultaneous with Gluconeogenesis

[Glu]blood

Meal

Insulin

Glucagon

Fed

Fast early

late fast

Glycogen gone

6-12 hrs1-2 hrs

3 daysLong Term Fast

Fatty Acid MetabolismFatty Acid Synthesis (liver & adipose)

Gluconeogenesis

b-oxidation [AcetylCoA] & Ketone Bodies made

Liver

Glucose

AcetylCoA

Pyruvate

NADH/FADH2

KrebsCycle

C6

C4

C5

C4

ATP

Bridging Rx.

Oxidative Phosphorylation

ADP O2

NAD+/FAD

Ketone Body Metabolism - Brain

AcetoacetylCoA

Ketone Bodies

From blood

The brain adapts (KBs cross blood-brain barrier)to obtain up to 75% ofEnergy from KBslong-term fast (~ 3 days)

[Glu]blood

Meal

Insulin

Glucagon

Fed

Fast early

late fast

Glycogen gone

6-12 hrs1-2 hrs

~ 3 days

Fasting Stateearly

late

long term

Brain adaptation to Ketone Bodies results in reduced destruction of body protein

[Glu]blood

Fed

Diabetes & Hyperglycemia

Liver Gluconeogenesis continues

180 mg/dl

Time 6-12 hrs

Meal

No Insulin

Leptin & Body Weight Regulation

Leptin is a peptide hormone secretedby subcutaneous fat - fat = leptin

Target is Hypothalmus: low [leptin] stimulates appetite high [leptin] suppresses appetite & may signal UCP expression?

Is Leptin a potential treatment for obesity?Or are people obese because they don’t respond to leptin?

Vasoconstrictor↑platelet aggregation

aspirin target

Vasodilator↓platelet aggregation

inflammationasthma and allergies

aka cyclooxygenases COX-1 and COX-2 clotting inflammation

eicosanoids

NSAIDs

Glucose

Acetyl CoA

cholesterol

cortisone

Membrane Lipids

arachadonic acid

prostaglandins (Cox-2)platelet activating factor(Cox-1)

leukotrienes

NSAIDs (aspirin)