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ACC regulation
Covalent Allosteric Transcriptional
FAS pathway
Dietary/Hormonal Learn chemical reactions
Stipanuk 351-364
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
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
Abetalipoproteinemia
Rare genetic disease No apo-B containing lipoproteins in plasma Cholesterol is ~25% of normal Mutation in MTP
Liver
Dietary TG
CE cholesterol Apo B48 Apo B48 CII FFA micelle A CIII chylomicron ER/golgi FFA-FABP TG TG/CE
enterocyte
Plasma
Type
B48
Association
Chylomicron
Function
Carry cholesterol esters Lacks LDL recpt binding domain
Binds LDL recpt. Activates LPL Inhibits LPL
A-1
Oxidation muscle
CIII
chylomicron
FFA
B48 TG/CE E
CII
FFA
Chylomicron remnant
G3P
Triglyceride storage adipose
liver
LPL
CIII
chylomicron
FFA
Glucose glut4
(+)
adipose
Triglycerides
LPL
CIII
FFA-albumin (oxidation)
chylomicron
FFA
adipose
Triglycerides
Ob mice
LPL synthesis and activity (adipocytes) LPL synthesis and activity (skeletal and heart muscle)
LPL synthesis and activity (adipocytes) LPL synthesis and activity (muscle)
LPL activity
Plasma
Dietary Carbohydrate
LIVER
glucose B48 TG/CE CMr cholesterol (exogenous) FFA FFA E LDL receptor
Acetyl CoA
mitochondria TG
Cholesterol (endogenous)
B100 CE/TG VLDL
TG
VLDL
-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)
Plasma
Dietary Carbohydrate
LIVER
glucose
pyruvate
Acetyl CoA
Acetyl CoA
FFA
FFA
TG
VLDL
VLDL
From liver
Cholesterol. In bile
LIVER
Endogenous cholesterol
B100 E CE/TG
LDL receptor
IDL
FA
B100 CE
LDL Extrahepatic tissue LDL receptor
adipose
Michael S. Brown
Joseph Goldstein
ACAT
HDL Formation
Liver
VLDL CE
FFA
CETP
LPL TG
IDL
TG
CETP
CE
HDL
LPL
FFA
Liver (LDL receptor) LDL
TG CETP CE
Extrahepatic tissues Cholesterol esters hydrolysis Free cholesterol ABCA1 A Pre-b-HDL LCAT A HDL CETP Cholesterol to VLDL, IDL,LDL Direct Liver
Cholesterol is reused or excreted in bile
These postprandial changes are beneficial in maintaining whole body homeostatsis of glycerides and cholesterol
VLDL
(+)
FA/TG
Acetyl CoA
Dietary Fat Intestinal Epithelium
(+)
Glucose
LDL
small intestine
extrahepatic tissue
Adipose, muscle
FFA
Atherogenic Particles
MEASUREMENTS:
Apolipoprotein B Non-HDL-C
VLDL
VLDLR
IDL
LDL
TG-rich lipoproteins
Thanks to Lipids Online: http://www.lipidsonline.org/
LDL
vascular endothelium (+) differentiate Oxidized LDL Macrophage LDL (+) (-) HDL
Arterial intima
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:819822
Next Week
Feb 23 Dr. Neile Edens Ross Labs Feb 25 Beta oxidation/Cholesterol Feb 27 Exam Review/Rough Draft revisions