review

1. Review ACC regulation Covalent Allosteric Transcriptional FAS pathway Dietary/Hormonal Learn chemical reactions

3. Overview Transport dietary lipids from intestine to liver (exogenous) Transport lipids from liver to peripheral tissues (endogenous) Lipoproteins Core of TG and CE Surface of phospholipids and some cholesterol Apolipoproteins (regulators of LP metabolism) CM, VLDL, IDL, LDL, HDL Clinical importance for disease

5. Exogenous Lipid Transport Fatty acids are absorbed by the apical microvilli of muscosal cells and resterified in the enterocyte (2 monoacylglyercol pathway). Apo B48 is the structural protein of the chylomicron and contain the majority of cholesterol (as cholesteryl ester) found in chylomicrons. Reesterfied TG are added to the chylomicron percurors via the action of a TG transfer protein. Apo B48 is then added. Apo CII is also added. This apoliprotein activates LPL activity. Nascent cylomicrons are assembled in the golgi apparatus and released from the enterocyte to enter the lymphatic system. Eventually chlyomicrons enter the plasma via the left thoracic lymph duct. Triglycerides and cholesterol esters are concentrated in the core of the chylomicron. Exogenous Lipid Transport Fatty acids are absorbed by the apical microvilli of muscosal cells and resterified in the enterocyte (2 monoacylglyercol pathway). Apo B48 is the structural protein of the chylomicron and contain the majority of cholesterol (as cholesteryl ester) found in chylomicrons. Reesterfied TG are added to the chylomicron percurors via the action of a TG transfer protein. Apo B48 is then added. Apo CII is also added. This apoliprotein activates LPL activity. Nascent cylomicrons are assembled in the golgi apparatus and released from the enterocyte to enter the lymphatic system. Eventually chlyomicrons enter the plasma via the left thoracic lymph duct. Triglycerides and cholesterol esters are concentrated in the core of the chylomicron.

7. Microsomal transfer protein helps in the assembly of protein and lipids that makeup lipoporteins. Lipoproteins are exported through a secretory pathway as water-soluble particles and circulate in blood.Microsomal transfer protein helps in the assembly of protein and lipids that makeup lipoporteins. Lipoproteins are exported through a secretory pathway as water-soluble particles and circulate in blood.

8. Microsomal Transfer Protein

9. Abetalipoproteinemia Rare genetic disease No apo-B containing lipoproteins in plasma Cholesterol is ~25% of normal Mutation in MTP

10. Fatty acids are absorbed by the apical microvilli of muscosal cells and resterified in the enterocyte (2 monoacylglyercol pathway). Apo B48 is the structural protein of the chylomicron and contain the majority of cholesterol (as cholesteryl ester) found in chylomicrons. Reesterfied TG are added to the chylomicron percurors via the action of a TG transfer protein. Apo B48 is then added. Apo CII is also added. This apoliprotein activates LPL activity. Nascent cylomicrons are assembled in the golgi apparatus and released from the enterocyte to enter the lymphatic system. Eventually chlyomicrons enter the plasma via the left thoracic lymph duct. Triglycerides and cholesterol esters are concentrated in the core of the chylomicron.Fatty acids are absorbed by the apical microvilli of muscosal cells and resterified in the enterocyte (2 monoacylglyercol pathway). Apo B48 is the structural protein of the chylomicron and contain the majority of cholesterol (as cholesteryl ester) found in chylomicrons. Reesterfied TG are added to the chylomicron percurors via the action of a TG transfer protein. Apo B48 is then added. Apo CII is also added. This apoliprotein activates LPL activity. Nascent cylomicrons are assembled in the golgi apparatus and released from the enterocyte to enter the lymphatic system. Eventually chlyomicrons enter the plasma via the left thoracic lymph duct. Triglycerides and cholesterol esters are concentrated in the core of the chylomicron.

12. Our chylomicron is destined for the liver. However on its journey this particle will encounter lipoprotein lipase which will hydrolyze TG present in the chylomicron. This will result in an overall reduction in the size of the chylomicron as TG is removed. CII is required for LPL activation. As the CM loses TG CII will then disassociate from the particle and LPL activity will no longer be supported. This particle is now called a chylomicron remnant and is destined for the liver. Insulin High in Fed State Fed state � Chylomicron synthesis is high. LPL activity is high. Storage of FFA as TG in adipose is high. Fasted state- Chylomicron synthesis is low. LPL activity in adipose is low while LPL activity in heart and other muscles remains steady. In addition LPL on surface of heart has a higher affinity (lower Km) for lipoprotein substrates. Therefore TG hydrolysis by the heart is determined by lipoprotein lipase levels (not the concentration of circulating lipoproteins). Heart LPL is saturated, even at low levels of circulating lipoproteins (fasted state). This ensures that the heart has preference for energy.Our chylomicron is destined for the liver. However on its journey this particle will encounter lipoprotein lipase which will hydrolyze TG present in the chylomicron. This will result in an overall reduction in the size of the chylomicron as TG is removed. CII is required for LPL activation. As the CM loses TG CII will then disassociate from the particle and LPL activity will no longer be supported. This particle is now called a chylomicron remnant and is destined for the liver. Insulin High in Fed State Fed state � Chylomicron synthesis is high. LPL activity is high. Storage of FFA as TG in adipose is high. Fasted state- Chylomicron synthesis is low. LPL activity in adipose is low while LPL activity in heart and other muscles remains steady. In addition LPL on surface of heart has a higher affinity (lower Km) for lipoprotein substrates. Therefore TG hydrolysis by the heart is determined by lipoprotein lipase levels (not the concentration of circulating lipoproteins). Heart LPL is saturated, even at low levels of circulating lipoproteins (fasted state). This ensures that the heart has preference for energy.

13. Fed state: High adipose LPL. Increased glucose transport into adipocyte.Fed state: High adipose LPL. Increased glucose transport into adipocyte.

14. During periods of low Insulin to glucagon, like a ketogenic diet (high protein. Low carbohydrate) the majority of fatty acids will be bound to albumin and utilized for B-oxidation (we will discuss b-ox during next lecture). This occurs because the reesterification of Fatty acids in the adipose is reduced due to limited G3P from glucose! Low insulin will also downregulate the glut4 receptor and lower glucose uptake into adipocyteDuring periods of low Insulin to glucagon, like a ketogenic diet (high protein. Low carbohydrate) the majority of fatty acids will be bound to albumin and utilized for B-oxidation (we will discuss b-ox during next lecture). This occurs because the reesterification of Fatty acids in the adipose is reduced due to limited G3P from glucose! Low insulin will also downregulate the glut4 receptor and lower glucose uptake into adipocyte

15. LPL: �Metabolic Gatekeeper?� LPL deficiency (chylomicronaemia) Massive accumulation of chylomicron-TG in plasma Cannot clear TG normally Normal fat storage and body weight ???!?!? How? Knockout mice � lethal LPL overexpression Decrease plasma TG Increase FA uptake in skeletal muscle Protect against obesity when fed high-fat diet

18. Regulation of Lipoprotein Lipase LPL is differentially regulated depending on the tissue. In the fed state LPL activity in adipocytes to promote storage of TG. In the fasted/exercised state, LPL activity in the muscle is activated or unchanged. The Km for muscle LPL is lower than that of LPL in adipose. Therefore substrates have a higher affinity for muscle LPL . The ensures that muscle LPL is always saturated regardless of TG levels and that cardiac tissues have first preference for circulating TGs.LPL is differentially regulated depending on the tissue. In the fed state LPL activity in adipocytes to promote storage of TG. In the fasted/exercised state, LPL activity in the muscle is activated or unchanged. The Km for muscle LPL is lower than that of LPL in adipose. Therefore substrates have a higher affinity for muscle LPL . The ensures that muscle LPL is always saturated regardless of TG levels and that cardiac tissues have first preference for circulating TGs.

19. Liver removes the chylomicron remnant via the remanant receptor.. Liver removes the chylomicron remnant via the remanant receptor..

21. Endogenous Lipid Transport

22. The liver synthesizes VLDL primarily during the fed state. Some of the TG present in the VLDL are synthesized de novo from dietary carbohydrate. Circulating concentrations of VLDL triacylglycerol increase after a carbohydrate rich meal. Other fatty acids of VLDL originate from free fatty acids internalized from plasma by liver. The cholesterol esters present in VLDL are from de novo synthesisThe liver synthesizes VLDL primarily during the fed state. Some of the TG present in the VLDL are synthesized de novo from dietary carbohydrate. Circulating concentrations of VLDL triacylglycerol increase after a carbohydrate rich meal. Other fatty acids of VLDL originate from free fatty acids internalized from plasma by liver. The cholesterol esters present in VLDL are from de novo synthesis

23. VLDL from liver enters plasma. VLDL contains B100 (structural, binds to LDL receptor), apo E (binds to LDL receptor) and CII (activates lipase). LPL works on VLDL and IDL to remove FFA. VLDL from liver enters plasma. VLDL contains B100 (structural, binds to LDL receptor), apo E (binds to LDL receptor) and CII (activates lipase). LPL works on VLDL and IDL to remove FFA.

24. Nobel Prize Alert: 1985

26. Function of LDL receptor Endocytosis of LDL and other LP Release free cholesterol into liver Incorporate into plasma membrane Inhibit new LDL receptors Inhibit cholesterol synthesis Promote ACAT activity (FC -> CE) � Regulated by SREBP monitors free cholesterol

27. HDL Formation

28. Interrelationship between lipoproteins. PLTP transfers phospholipids (lecithin) from VLDL, IDL and LDL to HDL.LCAT associated with HDL esterifies cholesterol. CETP transfers CE from HDL to VLDL, IDL and LDLInterrelationship between lipoproteins. PLTP transfers phospholipids (lecithin) from VLDL, IDL and LDL to HDL.LCAT associated with HDL esterifies cholesterol. CETP transfers CE from HDL to VLDL, IDL and LDL

29. Free cholesterol and lecithin (phospholipid) are transferred from cell membranes to pre B-HDL to form discoidal HDL. Via lymph this HDL enters the plasma. Through the action of LCAT (lecithin:cholesterol acyltransferase) the discoidal HDL becomes spheroidal and cholesterol is esterified. About 1/3 of the cholesterol present in HDL is moved to B-100 containing lipoproteins (IDL/LDL/VLDL) in exchange for TG (2). Cholesterol ester transfer protein mediates this transfer. The majority of the HDL/cholesterol is internalized by liver and to a lesser extent by adrenal and gonadal cells via the SR-BI scavenger protein for use in bile acid and steroid hormone synthesis.Free cholesterol and lecithin (phospholipid) are transferred from cell membranes to pre B-HDL to form discoidal HDL. Via lymph this HDL enters the plasma. Through the action of LCAT (lecithin:cholesterol acyltransferase) the discoidal HDL becomes spheroidal and cholesterol is esterified. About 1/3 of the cholesterol present in HDL is moved to B-100 containing lipoproteins (IDL/LDL/VLDL) in exchange for TG (2). Cholesterol ester transfer protein mediates this transfer. The majority of the HDL/cholesterol is internalized by liver and to a lesser extent by adrenal and gonadal cells via the SR-BI scavenger protein for use in bile acid and steroid hormone synthesis.

30. Reverse Cholesterol Transport : Direct

32. Postprandial Changes in Plasma Lipid Metabolism

33. Dietary Regulation of Lipoprotein Synthesis Dietary fat induces CM formation in intestine Increased availability of fatty acids stimulates VLDL synthesis Stimulation of fatty acid synthesis increases VLDL synthesis (carbohydrates and alcohol) Insulin release also increases VLDL productionDietary fat induces CM formation in intestine Increased availability of fatty acids stimulates VLDL synthesis Stimulation of fatty acid synthesis increases VLDL synthesis (carbohydrates and alcohol) Insulin release also increases VLDL production

38. Monocytes are mononuclear phagocytes that circulate in blood (white blood cells). Monocytes can emigrate from blood into tissues in the body and differentiate in macrophages. In response to cellular injury monocyte infiltrates arterial intima where it differentiates into a macrophage. Macrophage release cytokines and other pro-inflammatory agents. Macrophages can also accumulate lipids and form foam cells. Foam cells can release growth factors and also metalloproteinases which can lead to matrix degradation. Oxidized LDL can promote monocyte differentiation into macrophages. Oxidized LDL can also be taken up by macrophage receptors and lead to the formation of lipid rich foam cells. HDL cholesterol promotes cholesterol efflux from extrahepatic tissues and thus can reduce the transformation of macrophages into foam cells and thus reduce fatty streak (foam cell)Monocytes are mononuclear phagocytes that circulate in blood (white blood cells). Monocytes can emigrate from blood into tissues in the body and differentiate in macrophages. In response to cellular injury monocyte infiltrates arterial intima where it differentiates into a macrophage. Macrophage release cytokines and other pro-inflammatory agents. Macrophages can also accumulate lipids and form foam cells. Foam cells can release growth factors and also metalloproteinases which can lead to matrix degradation. Oxidized LDL can promote monocyte differentiation into macrophages. Oxidized LDL can also be taken up by macrophage receptors and lead to the formation of lipid rich foam cells. HDL cholesterol promotes cholesterol efflux from extrahepatic tissues and thus can reduce the transformation of macrophages into foam cells and thus reduce fatty streak (foam cell)

40. Journal Papers and Revision Out of 10 points Revisions � 30 pts Clear, concise writing Extend discussion � Additional references- email author w/ ? and include in revised report Current and future research

41. Next Week Feb 23 � Dr. Neile Edens � Ross Labs Feb 25 � Beta oxidation/Cholesterol Feb 27 � Exam Review/Rough Draft revisions