Download - Lipoproteinat
Review
• ACC regulation– Covalent– Allosteric– Transcriptional
• FAS pathway– Dietary/Hormonal – Learn chemical reactions
Transport of Fat: Lipoproteins
Stipanuk 351-364
I. ChylomicronsII. Triglyceride storage in adiposeIII. VLDL, LDL, IDL, HDLIV. Reverse Cholesterol TransportV. Medical implicationsVI. Nutritional regulation of lipoproteins
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
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
Microsomal Transfer Protein
Gordon et al. Trends in Cell Biology 5:1995
Lipid exchange protein
Heterodimer (55 kDa/97 kDa)
Protein disulphide isomerase
Defects in MTP
Abetalipoproteinemia
• Rare genetic disease
• No apo-B containing lipoproteins in plasma
• Cholesterol is ~25% of normal
• Mutation in MTP
Dietary TG
FFA FFA-FABP
micelle
enterocyte
ER/golgi
Apo B48
TGTG/CE
Apo B48
chylomicron
cholesterol
CE
Plasma
Liver
CII
CIII
A
B48 Chylomicron Carry cholesterol estersLacks LDL recptbinding domain
B100 VLDL,IDL,LDL Binds LDL recpt.
C-II Chyl. VLDL, IDL, HDL Activates LPL
C-III Chyl. VLDL, IDL, HDL Inhibits LPL
E Chyl. Remnant, VLDL, IDL Binds LDL recptHDL
A-1 HDL/Chylomicron LCAT activator(lecithin:cholesterol
acyltransferase)
Type Association Function
TG/CE
B48
LipoproteinLipase
Plasma
FFA
FFA
G3P
Triglyceridestorage
CII
adipose
TG/CE
B48 CII
muscle
LipoproteinLipase
FFA
chylomicron
Chylomicron remnantliver
CIII
CIII
Oxidation
TG
E
Fat accumulation in adipose: High I/G (Fed)
FFA
adipose
Glucose
InsulinregulatedglucosetransportCoA
Fatty acyl CoAG3P
Triglycerides
TG/CE
B48CII
CIII
LPL
Capillary endothelium
insulin(+)
(+)glut4
chylomicron
Fat accumulation in adipose: Low I/G (ketogenic)
FFA
adipose
Glucose
InsulinregulatedglucosetransportCoA
Fatty acyl CoA
G3P
Triglycerides
TG/CE
B48CII
CIII
LPL
Capillary endothelium
insulin(-)
(-)
glut4
chylomicron
FFA-albumin (oxidation)
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
Hormones and Adipose Tissue
-Adipose tissue is not just a big fat depot
-Produces a number of hormones that regulate fat storage
1. Leptin – decrease food intake/increase energy utilization * Adequate fat store = release leptin = decrease food intake and increase energy utilization
2. Acylating stimulating protein (ASP) chylomicrons stimulate production of ASP similar anabolic effects as insulin (different mechanisms) Promote adipocyte glucose uptake and FA reesterification
Ob mice
Regulation of Lipoprotein Lipase
Fed state - LPL synthesis and activity (adipocytes)
Fasted/ -exercisestate
LPL synthesis and activity (muscle)
LPL synthesis and activity (skeletal and heart muscle)
LPL synthesis and activity (adipocytes)
Lactating -Mammary gland
LPL activity
TG/CE
B48
cholesterol(exogenous)
CE/TG
B100
Dietary Carbohydrate
glucose pyruvate Acetyl CoA
mitochondriaAcetyl CoA
TG
FFA FFA TG VLDL
LIVER
VLDL
CMr Cholesterol(endogenous)
E
LDL receptor
Plasma
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)
Endogenous Lipid Transport
cholesterol(exogenous)
CE/TG
B100
Dietary Carbohydrate
glucose pyruvate Acetyl CoA
mitochondriaAcetyl CoA
TG
FFA FFA TG VLDL
LIVER
VLDL
Cholesterol(endogenous)
Plasma
CE/TG
B100
VLDL
E
CII
From liver
LPL
FFA
adiposemuscle
CE/TG
IDL
B100 ELDL receptor
CE
LDL
E
FA
B100
LIVER
Endogenous cholesterol
Extrahepatic tissue
Cholesterol.In bile
LDL receptor
Nobel Prize Alert: 1985
Michael S. Brown Joseph Goldstein
A Receptor-Mediated Pathway for Cholesterol Homeostasis
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
HDL Formation
Liver
ApoA
Pre--HDL
Discoidal/lipid poor
Cholesterol fromLiver and intestinal Cells via ABCA1
Pre--HDL
A A
Unesterified cholesterol-rich
Lecithin-cholesterol acyltransferase (LCAT)
HDL
1. Cholesterol to liver
Steroidogeniccells
2. Cholesterol for steroid synthesis
Cholesterolto otherlipoproteins
3. Cholesterol-estertransfer protein(CETP)
A
VLDL
IDL
LDL
LPL
LPL
FFA
FFA
Liver(LDL receptor)
Liver(LDL receptor)
HDL
CETP
CE
TG
CETP
TG
CE
CETP
TG
CE
CETP exchanges cholesterol esters in HDLs for triglycerides in B100 LPs
CETPLCAT
Free cholesterol
hydrolysis
Reverse Cholesterol Transport: Indirect
Extrahepatic tissues
Cholesterol esters
Pre--HDL
A
HDLACholesterol to VLDL, IDL,LDL
LiverCholesterol is reusedor excreted in bile
ABCA1
Direct
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
Exchange of cholesterol for VLDL TG in HDL (CETP)
Transfer of cholesterol from cells into plasmareverse transport of cholesterol from peripheral tissue to liver
LCAT activity = esterification of free cholesterol (HDL)
These postprandial changes are beneficial in maintainingwhole body homeostatsis of glycerides and cholesterol
Dietary Regulation of Lipoprotein Synthesis
Intestinal Epithelium
Chylomicron
Dietary Fat
(+)
Chylomicron Synthesis VLDL Synthesis (Liver)
Glucose
VLDLHigh CARBInsulin
(+)
Acetyl CoA
FA/TG
(+)
Dietary fat
smallintestine
capillaries
Lipoprotein Lipase
FFAAdipose, muscle
chylomicronschylomicronsreminants
VLDL
Lipoprotein Lipase
FFA
extrahepatictissue
IDL
HDL
LDL
Endogenouscholesterol
Exogenous cholesterol
Bile salts
Liver
Atherogenic ParticlesAtherogenic Particles
Apolipoprotein BApolipoprotein B
Non-HDL-CNon-HDL-CMEASUREMENTS:MEASUREMENTS:
TG-rich lipoproteinsTG-rich lipoproteins
VLDLVLDL VLDLVLDLRRIDLIDL LDLLDL Small,Small,
densedenseLDLLDL
Thanks to Lipids Online: http://www.lipidsonline.org/
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
Hypertriglyceridemia and CHD Risk: Associated Abnormalities
Relationship between HDL/LDL and heart disease:One Theory
Monocyte (white blood cell)
vascular endothelium
Arterial intima
Macrophage
Oxidized LDL(+)
LDL
LDL (+)
Foam cells (fatty streak)
(-) HDL
Cholesterol to liver
differentiate
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:819–8222. McConnell MV et al. Am J Cardiol 1997;80:1226–1228
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
Next Week
• Feb 23 – Dr. Neile Edens – Ross Labs
• Feb 25 – Beta oxidation/Cholesterol
• Feb 27 – Exam Review/Rough Draft
revisions