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Today’s topics: Fatty Acid Metabolism Cholesterol Biosynthesis

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.

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Today’s topics: Fatty Acid Metabolism Cholesterol Biosynthesis

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  1. Today’s topics: Fatty Acid Metabolism Cholesterol Biosynthesis Catabolic - Lipases and b-oxidation

  2. to blood Lipase Triglyceride (Fat) O CH2-O - C-R | O CH–O - C-R | O CH2-O - C-R  insulin Glycerol + 3 Fatty Acids  glucagon Fatty Acids transported by Serum Albumin in blood Both Liver & Muscle can oxidize Fatty Acids. Brain cells can’t metabolize Fatty Acids (can’t enter)

  3. Insulin Fatty Acid Synthesis Fed State glucagon [Glu] blood Meal Insulin (& citrate) stimulate AcetylCoAcarboxylase Glucagon/epinephrine inhibit Glucagon stimulates Lipase activity in adipose. Fatty Acids released to blood to be used as fuel by other cells. Fasting State

  4. Glucagon effect on adipose

  5. HSA with 8 myristate (green) – Trp214 (purple) Serum Albumin transports FAs in blood II I III

  6. Ibuprofen – Drug site II in Domain IIIA of HSA with secondary site in domain II II W214 I III

  7. b – Oxidation (what?) Palmitate (C16) + 7FAD + 7NAD+ + ATP + 8 CoASH Net reaction 8Acetyl CoA + 7FADH2 + 7NADH, H+ + AMP + 2Pi Fatty Acid + ATP + CoASH→ (Fatty Acyl CoA)n + AMP + PPi activation step PPi 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

  8. H HHH O - C – C – C – Cb – Ca– C –SCoA FAD H H O - C – C – C – Cb – Ca– C –SCoA dehydrogenase FADH2 H2O OHHHH O - C – C – C – Cb – Ca– C –SCoA NAD+ O H H O - C – C – C – Cb – Ca– C – SCoA dehydrogenase NADH,H+ CoASH O O - C – C – C – Cb– SCoA + CH3– C –SCoA

  9. Fatty acid catabolism Glucose Fat (triglycerides) Lipase Glycolysis Fatty acids Pyruvate Why? Utilize energy stores Where? Liver & Muscle (not in brain) When? Fasting State Bridging Rx. b-oxidation AcetoacetylCoA AcetylCoA NAD+/FAD NADH/FADH2 C6 C4 Oxidative Phosphorylation Krebs Cycle ADP O2 C5 C4 ATP

  10. Fatty Acid Metabolism 3 days Long Term Fast High Fat use [AcetylCoA] Liver Gluconeogenesis provides glucose to blood/brain.

  11. Fat Metabolism - Liver Glucose Fat (triglycerides) X To blood Fatty acids Pyruvate b-oxidation Bridging Rx. Ketone Bodies acetoacetate b-hydroxybutyrate acetone AcetoacetylCoA AcetylCoA Ketone Body Formation X NAD+/FAD NADH/FADH2 C6 C4 Krebs Cycle Gluconeogenesis Oxidative Phosphorylation ADP O2 C5 C4 ATP

  12. O || CH3 - C - CH3 acetone O || CH3 - C - CH2 - COO- OH | CH3 - CH - CH2 - COO- acetoacetate  - hydroxy butyrate to blood Ketone Body Formation What: acetylCoAketone bodies Why: provide blood with fuel alternate to glucose to minimize protein breakdown Where: Liver When: Fasting State - Late & Long-term simultaneous with Gluconeogenesis Ketone Bodies

  13. Fatty Acid Synthesis (liver & adipose) b-oxidation [AcetylCoA] & Ketone Bodies made Liver Gluconeogenesis Fatty Acid Metabolism 3 days Long Term Fast

  14. Ketone Body Metabolism - Brain Glucose The brain adapts (KBs cross blood-brain barrier) to obtain up to 75% of Energy from KBs long-term fast (~ 3 days) From blood Pyruvate Bridging Rx. Ketone Bodies AcetoacetylCoA AcetylCoA NAD+/FAD NADH/FADH2 C6 C4 Krebs Cycle Oxidative Phosphorylation ADP O2 C5 C4 ATP

  15. early long term ~ 3 days late Brain adaptation to Ketone Bodies results in reduced destruction of body protein Fasting State

  16. No Insulin [Glu] blood Meal Diabetes & Hyperglycemia 180 mg/dl Fed Time 6-12 hrs Liver Gluconeogenesis continues

  17. Leptin & Body Weight Regulation Leptin is a peptide hormone secreted by 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?

  18. inflammation asthma and allergies aka cyclooxygenases COX-1 and COX-2 clotting inflammation aspirin target Vasodilator ↓platelet aggregation Vasoconstrictor ↑platelet aggregation

  19. eicosanoids

  20. NSAIDs Membrane Lipids arachadonic acid prostaglandins (Cox-2) platelet activating factor (Cox-1) leukotrienes Glucose Acetyl CoA cholesterol cortisone NSAIDs (aspirin)

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