Review• ACC regulation  – Covalent  – Allosteric  – Transcriptional• FAS pathway  – Dietary/Hormonal  – Learn chemical rea...
Transport of Fat: LipoproteinsI. ChylomicronsII. Triglyceride storage in adiposeIII. VLDL, LDL, IDL, HDLIV. Reverse Choles...
Overview• Transport dietary lipids from intestine to liver  (exogenous)• Transport lipids from liver to peripheral tissues...
Chylomicron Assembly-assembled in enterocyte golgi/ER-Apolipoprotein (Apo) B organizes assembly       -B48- Requires phosp...
Microsomal Transfer Protein                                              Lipid exchange protein                           ...
Abetalipoproteinemia• Rare genetic disease• No apo-B containing lipoproteins in  plasma• Cholesterol is ~25% of normal• Mu...
LiverDietary TG                           CE   Apo B48             cholesterol                                            ...
Type     Association                    FunctionB48     Chylomicron                Carry cholesterol esters               ...
Plasma                                                                          TG                  B48                   ...
Fat accumulation in adipose: High I/G (Fed)                               Capillary endothelium                           ...
Fat accumulation in adipose: Low I/G (ketogenic)                               Capillary endothelium                      ...
LPL: “Metabolic Gatekeeper?”• LPL deficiency (chylomicronaemia)  –   Massive accumulation of chylomicron-TG in plasma  –  ...
Hormones and Adipose Tissue-Adipose tissue is not just a big fat depot-Produces a number of hormones that regulate fat sto...
Ob mice
Regulation of Lipoprotein LipaseFed state   -   LPL synthesis and activity (adipocytes)                LPL synthesis and a...
Plasma             Dietary Carbohydrate                                            LIVER                  glucose        p...
Dietary factors affecting Chylomicron and Chylomicron remnant clearance   -elevated postprandial lipoproteins and cardiova...
Endogenous Lipid Transport
Plasma          Dietary Carbohydrate                                        LIVER               glucose       pyruvate    ...
From liver               Cholesterol.                          In bile                  LIVER                             ...
Nobel Prize Alert: 1985A Receptor-Mediated Pathway for Cholesterol Homeostasis    Michael S. Brown               Joseph Go...
Function of LDL receptor•    Endocytosis of LDL and other LP•    Release free cholesterol into liver    1.   Incorporate i...
HDL Formation                                            Steroidogenic                                                    ...
CETP exchanges cholesterol esters in HDLs for triglycerides in B100 LPs                              VLDL                 ...
Reverse Cholesterol Transport: IndirectExtrahepatic tissues                                                       Liver Ch...
Reverse Cholesterol Transport :           Direct     SR-BI (scavenger receptor, class B, type 2)
1. LCAT deficiency?2. CETP deficiency?3. apo AI deficiency?
Postprandial Changes in Plasma         Lipid Metabolism    Fat storage via LPL    Transfer of cholesterol from cells into ...
Dietary Regulation of Lipoprotein             SynthesisChylomicron Synthesis                     VLDL Synthesis (Liver)   ...
LDL                                                 Liver              Dietary fat       Bile salts   Endogenous          ...
Atherogenic Particles                                                  Apolipoprotein B        MEASUREMENTS:              ...
Hypertriglyceridemia and CHD Risk:          Associated Abnormalities Accumulation of chylomicron remnants Accumulation o...
Relationship between HDL/LDL and heart disease:                  One Theory      Monocyte (white blood cell)              ...
Alcohol Increases HDL-C Level• Alcohol increases HDL-C level in a dose-dependent  manner.• Half bottle of wine per day (39...
Journal Papers and RevisionOut of 10 pointsRevisions – 30 ptsClear, concise writingExtend discussion –  Additional referen...
Next Week• Feb 23 – Dr. Neile Edens – Ross Labs• Feb 25 – Beta oxidation/Cholesterol• Feb 27 – Exam Review/Rough Draft    ...
Lipoproteinat
Lipoproteinat
Lipoproteinat
Lipoproteinat
Lipoproteinat
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Lipoproteinat

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  • 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.
  • 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.
  • 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.
  • 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.
  • Fed state: High adipose LPL. Increased glucose transport into adipocyte.
  • 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 adipocyte
  • 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.
  • Liver removes the chylomicron remnant via the remanant receptor..
  • 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 synthesis
  • 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.
  • 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 LDL
  • 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.
  • 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 production
  • 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)
  • Lipoproteinat

    1. 1. Review• ACC regulation – Covalent – Allosteric – Transcriptional• FAS pathway – Dietary/Hormonal – Learn chemical reactions
    2. 2. Transport of Fat: LipoproteinsI. ChylomicronsII. Triglyceride storage in adiposeIII. VLDL, LDL, IDL, HDLIV. Reverse Cholesterol TransportV. Medical implicationsVI. Nutritional regulation of lipoproteins Stipanuk 351-364
    3. 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
    4. 4. Chylomicron Assembly-assembled in enterocyte golgi/ER-Apolipoprotein (Apo) B organizes assembly -B48- Requires phospholipids-2 forms of apo B -B100, large- liver -B48, smaller – intestine- Picks up apo A,C and E in plasma- TG composition closely resembles dietary intake
    5. 5. Microsomal Transfer Protein Lipid exchange protein Heterodimer (55 kDa/97 kDa) Protein disulphide isomerase Defects in MTPGordon et al. Trends in Cell Biology 5:1995
    6. 6. Abetalipoproteinemia• Rare genetic disease• No apo-B containing lipoproteins in plasma• Cholesterol is ~25% of normal• Mutation in MTP
    7. 7. LiverDietary TG CE Apo B48 cholesterol Apo B48 CII FFA FFA-FABP TG TG/CE micelle A CIII chylomicron ER/golgi enterocyte Plasma
    8. 8. Type Association FunctionB48 Chylomicron Carry cholesterol esters Lacks LDL recpt binding domainB100 VLDL,IDL,LDL Binds LDL recpt.C-II Chyl. VLDL, IDL, HDL Activates LPLC-III Chyl. VLDL, IDL, HDL Inhibits LPLE Chyl. Remnant, VLDL, IDL Binds LDL recpt HDLA-1 HDL/Chylomicron LCAT activator (lecithin:cholesterol acyltransferase)
    9. 9. Plasma TG B48 FFA Oxidation CII muscle TG/CE Lipoprotein CIII Lipase chylomicron Lipoprotein B48 CII FFA Lipase TG/CE CIII FFA E Chylomicron remnant G3P liver Triglyceride adipose storage
    10. 10. Fat accumulation in adipose: High I/G (Fed) Capillary endothelium (+) B48 insulin CII LPL TG/CECIII chylomicron FFA Glucose glut4 (+) Insulin regulated glucose CoA transport G3P Fatty acyl CoA Triglycerides adipose
    11. 11. Fat accumulation in adipose: Low I/G (ketogenic) Capillary endothelium (-) B48 insulin CII LPL TG/CE FFA-albumin (oxidation)CIII chylomicron FFA Glucose (-) Insulin glut4 regulated glucose CoA transport G3P Fatty acyl CoA Triglycerides adipose
    12. 12. 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
    13. 13. Hormones and Adipose Tissue-Adipose tissue is not just a big fat depot-Produces a number of hormones that regulate fat storage1. Leptin – decrease food intake/increase energy utilization * Adequate fat store = release leptin = decrease food intake and increase energy utilization2. Acylating stimulating protein (ASP) chylomicrons stimulate production of ASP similar anabolic effects as insulin (different mechanisms) Promote adipocyte glucose uptake and FA reesterification
    14. 14. Ob mice
    15. 15. Regulation of Lipoprotein LipaseFed state - LPL synthesis and activity (adipocytes) LPL synthesis and activity (skeletal and heart muscle)Fasted/ - LPL synthesis and activity (adipocytes)exercise LPL synthesis and activity (muscle)state Lactating - LPL activity Mammary gland
    16. 16. Plasma Dietary Carbohydrate LIVER glucose pyruvate Acetyl CoAB48 LDL receptor Acetyl CoA E mitochondriaTG/CE TG CMr Cholesterol cholesterol (endogenous) B100 (exogenous) CE/TG VLDL FFA FFA TG VLDL
    17. 17. Dietary factors affecting Chylomicron and Chylomicron remnant clearance -elevated postprandial lipoproteins and cardiovascular disease -Diets rich in PUFA can reduce postprandial TG response -compared to diets rich in SFA -Increased LPL activity = Increased TG clearance from CM -Preferential hydrolysis of PUFA-containing CM -Increased clearance of CMr -Human data are less convincing than animal studies -Omega 3 > Omega 6 > SFA -Not much work with MUFA although may be helpful (OLIVE OIL)
    18. 18. Endogenous Lipid Transport
    19. 19. Plasma Dietary Carbohydrate LIVER glucose pyruvate Acetyl CoA Acetyl CoA mitochondria cholesterol (exogenous) TG Cholesterol (endogenous) B100 CE/TG VLDL FFA FFA TG VLDL
    20. 20. From liver Cholesterol. In bile LIVER Endogenous cholesterol B100 E CII CE/TG VLDL B100 E LDL receptor CE/TG IDL E B100 LPL FA CE FFA LDL Extrahepatic tissuemuscle adipose LDL receptor
    21. 21. Nobel Prize Alert: 1985A Receptor-Mediated Pathway for Cholesterol Homeostasis Michael S. Brown Joseph Goldstein
    22. 22. Function of LDL receptor• Endocytosis of LDL and other LP• Release free cholesterol into liver 1. Incorporate into plasma membrane 2. Inhibit new LDL receptors 3. Inhibit cholesterol synthesis 4. Promote ACAT activity (FC -> CE)• Regulated by SREBP monitors free cholesterol Free cholesterol = LDL receptors, chol. synthesis ACAT
    23. 23. HDL Formation Steroidogenic cells Cholesterol to other 2. Cholesterol lipoproteins for steroid Liver synthesis 3. Cholesterol-ester 1. Cholesterol transfer protein to liver (CETP) A HDL ApoA Lecithin-cholesterol acyl transferase (LCAT) A A Pre-β-HDL Cholesterol from Liver and intestinal Pre-β-HDL Cells via ABCA1Discoidal/lipid poor Unesterified cholesterol-rich
    24. 24. CETP exchanges cholesterol esters in HDLs for triglycerides in B100 LPs VLDL CE CETP FFA LPL TGLiver IDL TG(LDL receptor) HDL CETP CE LPL FFA TG CETPLiver CE(LDL receptor) LDL
    25. 25. Reverse Cholesterol Transport: IndirectExtrahepatic tissues Liver Cholesterol esters Cholesterol is reused or excreted in bilehydrolysis Direct Free cholesterol ABCA1 A LCAT CETP Cholesterol to Pre-β-HDL A HDL VLDL, IDL,LDL
    26. 26. Reverse Cholesterol Transport : Direct SR-BI (scavenger receptor, class B, type 2)
    27. 27. 1. LCAT deficiency?2. CETP deficiency?3. apo AI deficiency?
    28. 28. Postprandial Changes in Plasma Lipid Metabolism Fat storage via LPL Transfer of cholesterol from cells into plasma reverse transport of cholesterol from peripheral tissue to liver Exchange of cholesterol for VLDL TG in HDL (CETP) LCAT activity = esterification of free cholesterol (HDL)These postprandial changes are beneficial in maintainingwhole body homeostatsis of glycerides and cholesterol
    29. 29. Dietary Regulation of Lipoprotein SynthesisChylomicron Synthesis VLDL Synthesis (Liver) Chylomicron VLDL (+) High CARB FA/TG Insulin (+) Acetyl CoA Dietary Fat Intestinal Epithelium (+) Glucose
    30. 30. LDL Liver Dietary fat Bile salts Endogenous cholesterol extrahepatic small Exogenous tissue intestine cholesterol HDL chylomicronschylomicrons reminants VLDL IDL capillaries Lipoprotein Lipase Lipoprotein Lipase FFA FFA Adipose, muscle
    31. 31. Atherogenic Particles Apolipoprotein B MEASUREMENTS: Non-HDL-C VLDL VLDLR IDL LDL Small, dense LDL TG-rich lipoproteinsThanks to Lipids Online: http://www.lipidsonline.org/
    32. 32. Hypertriglyceridemia and CHD Risk: Associated Abnormalities Accumulation of chylomicron remnants Accumulation of VLDL remnants Generation of small, dense LDL Association with low HDL Increased coagulability -  plasminogen activator inhibitor (PAI-1) -  factor VIIc - Activation of prothrombin to thrombin
    33. 33. Relationship between HDL/LDL and heart disease: One Theory Monocyte (white blood cell) Cholesterol to liver LDL vascular endothelium (+) differentiate Oxidized LDL Arterial intima Macrophage LDL (+) (-) HDL Foam cells (fatty streak)
    34. 34. Alcohol Increases HDL-C Level• Alcohol increases HDL-C level in a dose-dependent manner.• Half bottle of wine per day (39 g alcohol) for 6 weeks significantly increased mean HDL-C level by 7 mg/dL in 12 healthy subjects.1 – Wine intake did not significantly affect Total-C, Total-TG, or LDL-C.1• One beer per day (13.5 g alcohol) for 6 weeks significantly increased mean HDL-C level by 2 mg/dL in 20 healthy subjects.2 – Beer intake did not significantly affect LDL-C, VLDL-C, TG, or apolipoproteins. 1. Thornton J et al. Lancet 1983;ii:819–822 2. McConnell MV et al. Am J Cardiol 1997;80:1226–1228
    35. 35. Journal Papers and RevisionOut of 10 pointsRevisions – 30 ptsClear, concise writingExtend discussion – Additional references- email author w/ ? and include in revised report Current and future research
    36. 36. Next Week• Feb 23 – Dr. Neile Edens – Ross Labs• Feb 25 – Beta oxidation/Cholesterol• Feb 27 – Exam Review/Rough Draft revisions

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