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Today’s topics: Fatty Acid Metabolism Cholesterol Biosynthesis Catabolic - Lipases and b -oxidation. to blood. Lipase. Triglyceride (Fat). O CH 2 -O - C-R | O CH –O - C-R | O CH 2 -O - C-R. insulin . Glycerol + 3 Fatty Acids. - PowerPoint PPT Presentation
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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)