Substrates for lipid synthesis

1. Substrates for lipid synthesis Phosphatidate is a precursor of storage and membrane lipids Formed by the addition of two fatty acids to glycerol 3-phosphate

2. Triacylglycerol synthesis Triacylglycerol (TAG) synthesis is completed by TAG synthase complex bound to the endoplasmic reticulum The liver is the primary site of triacylglycerol synthesis Liver TAGs are transported to muscle for use as fuel or to adipose tissue for storage

3. Phospholipid synthesis • Phosphatidate is also a precursor for phospholipids • Phospholipid synthesis combines diacylglyceride with an alcohol, one of the components must be activated Ethanolamine Choline Inositol

4. Synthesis from an activated diacylglycerol • This reaction is driven by hydrolysis of PPi The activated phosphatidyl unit then reacts with the hydroxyl group of an alcohol

5. Synthesis from an activated alcohol • This reaction is driven by hydrolysis of PPi Phosphatidylethanolamine can be synthesized from CDP-ethanolamine Phosphatidylcholine is the most common phospholipid in humans Dietary cholineis activated in a series of reactions analogous to those in the activation of ethanolamine

6. Phosphatidylcholine may also be synthesized from phosphatidylethanolamine when dietary choline is insufficient • S-Adenosylmethionine is the methyl donor

7. Sphingolipids are synthesized from ceramide

12. b-N-acetyl hexosaminidase Tay Sachs disease results from the inability to degrade a ganglioside

13. Cholesterol synthesis • Cholesterol maintains proper fluidity of cell membranes and is the precursor of steroid hormones • De novo synthesis occurs predominantly in the liver • All 27 C atoms of cholesterol are derived from acetyl CoA • Synthesis begins with the formation of isopentenyl pyrophosphate (IPP), an activated isoprene unit • Six molecules of IPP condense to form squalene • Squalenecyclizesto a tetracyclic product that is converted to cholesterol

14. Isopentenyl pyrophosphate synthesis The synthesis of mevalonate is the committed step in cholesterol formation Mevalonate is converted to an activated 5-carbon isoprene 2 NADPH + 2 H+ HMG-CoA reductase Mevalonate HMG-CoA

15. Lovastatin is a competitive inhibitor of HMG-CoAreductase

16. Squalene synthesis • Squalene is synthesized from IPP • C5C10C15C30

17. Squalenecyclization

18. Regulation of cholesterol synthesis • The rate of cholesterol synthesis is responsive to the cellular levels of cholesterol • Cholesterol can be obtained from the diet or synthesized de novo • A person on a low cholesterol diet will synthesize about • 800 mg of cholesterol per day • Feedback inhibition is mediated primarily by changes in the amount and activity of HMG CoAreductase

19. When cholesterol levels are high: • ↓ Synthesis of reductase mRNA • ↓ Translation of reductase mRNA • ↑ Degradation of the reductase • ↑ Phosphorylationof the reductase, decreasing activity

20. Plasma lipoproteins transport cholesterol and triacylglycerols Lipoproteins are classified according to increasing density

21. Lipoprotein metabolism

22. Low-density lipoproteins play a central role in cholesterol metabolism

24. Familial hypercholesteremiais caused by failure of LDL • receptors and consequent high concentrations of • LDL cholesterol in the blood

25. Bile acids facilitate lipid absorption Bile acids are synthesized in the liver from cholesterol, stored and concentrated in the gall bladder and released into the small intestine 7α-Hydroxylase

26. Liver HMG CoA Glucose HMG CoA Reductase Cholesterol Levels LDL Receptor Cholesterol Absorption Blood Vessel LDL Small Intestines

27. Liver HMG CoA Glucose HMG CoA Reductase Cholesterol-7- -hydroxylase Cholesterol Levels LDL Receptor Bile Acid Pool Blood Vessel Re-absorption Gall Bladder LDL Small Intestines

28. Steroid hormones are signaling molecules that are synthesized from cholesterol Progesterone (a progestagen) prepares the uterus for implantation and the maintenance of pregnancy Testosterone (an androgen) directs the development of male secondary sex characteristics, including maintenance of the testes and development of muscle mass (thus testosterone is an anabolic steroid) Estrogens (eg, estradiol) direct female female secondary sex characteristics and participate in the ovarian cycle Glucocorticoids (eg, cortisol) promote gluconeogenesis and glycogen formation, enhance degradation of fat and protein and inhibit the inflammatory response Mineralocorticoids (egaldosterone) regulate salt balance, volume and pressure of the blood

30. Vitamin D is derived from cholesterol by the energy of sunlight Vitamin D plays an essential role in calcium and phosphorous metabolism