PLASMA LIPIDS

G M KELLERMAN
HUNTER AREA PATHOLOGY SERVICE

WHY MEASURE LIPIDS?

ATHEROMATOUS DEPOSITS ARE COMPOSED OF MIXED LIPIDS INCLUDING CHOLESTEROL, VARIOUS LIPOPROTEIN COMPONENTS (NATIVE OR VARIABLY DEGRADED), FIBRINOUS MATERIAL AND CELLS >50 YEARS AGO IT WAS FOUND THAT HIGH PLASMA CHOLESTEROL AND HIGH PLASMA LEVELS OF LOW DENSITY LIPOPROTEINS WERE ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO ATHEROSCLEROSIS FRAMINGHAM LONG TERM STUDY CONFIRMED THESE RISK FACTORS

PLASMA LIPOPROTEINS
FAT FORMS INSOLUBLE GLOBULES IN WATER AND SO NEEDS DETERGENT AND APOPROTEINS TO STABILISE THE EMULSION CHYLOMICRONS ARE ABSORBED FAT FROM GUT VLDL ARE FAT SECRETED BY LIVER CHYLOMICRON REMNANTS AND IDL ARE ON THE WAY TO REMOVAL LDL ARE FINAL STAGE OF THE ABOVE BEFORE UPTAKE INTO CELLS FOR RECYCLING HDL ARE MECHANISM TO TRANSPORT CHOLESTEROL TO LIVER AND TO REALLOCATE APOPROTEINS TO/FROM OTHER LIPOPROTEINS

APOLIPOPROTEINS
THERE ARE 4 CLASSES OF PROTEINS WHICH LOCALISE ON THE SURFACE OF LIPOPROTEINS, WHICH ARE MADE BY LIVER AND INTESTINE APO-A (A1, A2 AND A4) INTERACT WITH THE ENZYME LECITHIN-CHOLESTEROL ACYL TRANSFERASE (LCAT) THAT ESTERIFIES CHOLESTEROL APO B(B48, B100) ARE LARGE, ARE THE PRIMARY STABILISING PROTEINS AND ENABLE REMNANTS TO BIND TO THE B RECEPTORS ON MANY TYPES OF CELL APO-C (C1, C2, C3) INTERACT WITH LIPOPROTEIN LIPASE THAT BREAKS DOWN TRIGLYCERIDES FOR CELL UPTAKE, AND PERHAPS WITH LCAT ALSO APO-E (E2, E3, E4) ALONG WITH APO-B ENABLE REMNANTS OF LIPOPROTEINS TO BIND TO THE B-E RECEPTORS ON LIVER CELLS

CHYLOMICRONS
SECRETED BY INTESTINAL EPITHELIUM (2ND HALF OF ILEUM) FOLLOWING ABSORPTION OF DIETARY FAT LARGE TRIGLYCERIDE GLOBULES SECRETED WITH COATING OF PHOSPHOLIPID + CHOLESTEROL, APO-A AND APO-B48 PICK UP APO-C AND APO-E FROM HDL IN PLASMA APO-C2 ACTIVATES LIPOPROTEIN LIPASE WHICH ENABLES BREAKDOWN OF TRIGLYCERIDES AND THEIR ABSORPTION INTO CELLS APO-A1 ACTIVATES LCAT WHICH TRANSFERS A FATTY ACID FROM LECITHIN TO CHOLESTEROLTO MAKE CHOLESTEROL ESTER WHICH CAN TRANSFER FROM SURFACE TO INTERIOR THESE TWO ENZYMES ENABLE CHYLOMICRONS TO SHRINK TO REMNANTS APO-E + APO-B48 BIND TO LIVER CELL B-E RECEPTORS AND ENABLE REMNANTS TO BE TAKEN UP BY LIVER

VERY LOW DENSITY LIPOPROTEINS (VLDL)

SECRETED BY LIVER TO DISPOSE OF TRIGLYCERIDE SYNTHESISED FROM SUGARS OR FATTY ACIDS GLOBULES OF TRIGLYCERIDE (SMALLER THAN CHYLOMICRONS) SECRETED WITH COATING OF APO-B100, APO-C AND APO-E; PICK UP MORE APO-C FROM HDL IN CIRCULATION APO-C2 ACTIVATES LIPOPROTEIN LIPASE WHICH BREAKS DOWN TRIGLYCERIDE FOR CELL UPTAKE ONGOING INTERACTION WITH HDL ENABLES ESTERIFICATION OF CHOLESTEROL AND ACCUMULATION OF CHOLESTEROL ESTER INSIDE PARTICLE WHICH SHRINKS VIA IDL TO LDL, LOSING APO-C AND APO-E TO HDL LDL AS FINAL STAGE RETAINS CHOLESTEROL ESTER AND APO-B100, BINDS TO B RECEPTORS IN VARIOUS CELLS IDL MAY ALSO REACT WITH B-E RECEPTORS ON LIVER CELLS

LOW DENSITY LIPOPROTEINS LDL

THESE CONTAIN MOST OF THE PLASMA CHOLESTEROL (AS ESTER) + APO-B100 AND ARE TAKEN UP INTO CELLS VIA LDL RECEPTOR INSIDE CELLS THE CHOLESTEROL ESTER IS HYDROLYSED TO FORM FREE CHOLESTEROL AND THE APO-B100 IS BROKEN DOWN LDL HAVE A HALF LIFE OF 2-3 DAYS AND SOME MOLECULES BECOME ALTERED BY OXIDATION AND OTHER CHANGES ALTERED LDL (AND ? SOME NORMAL LDL) TAKEN UP BY SCAVENGER RECEPTORS ON MACROPHAGES TO FORM FOAM CELLS CHOLESTEROL IS USED BY CELLS IF NEEDED, OR REMOVED BY HDL FOR TRANSPORT BACK TO LIVER

HIGH DENSITY LIPOPROTEINS HDL

PRIMARY HDL CONTAIN MAINLY PHOSPHOLIPID AND APO-A1, BUT PICK UP OTHER APOPROTEINS (EXCEPT APO-B) FROM OTHER LIPOPROTEINS IN CIRCULATION THERE IS A CONSTANT EXCHANGE OF THE APOPROTEINS BETWEEN HDL AND THE SHRINKING CHYLOMICRONS AND VLDL HDL PICK UP CHOLESTEROL FROM CELLS AND ALSO FROM OTHER LIPOPROTEINS LCAT ENABLES THIS CHOLESTEROL TO BE ESTERIFIED ANOTHER PROTEIN, CHOLESTEROL ESTER TRANSFER PROTEIN, ENABLES EXCHANGE OF CHOLESTEROL ESTER FROM HDL TO LDL WHICH CAN BE TAKEN UP BY LIVER FINALLY HDL CAN TRANSFER THE CHOLESTEROL ESTERS DIRECTLY TO LIVER VIA B-E RECEPTORS OF SPECIFIC HDL RECEPTORS

CHOLESTEROL - SUMMARY
DIETARY CHOLESTEROL IS PARTLY ABSORBED AND JOINS THE POOL OF LIPOPROTEINS CHOLESTEROL IS CONSTANTLY LOST VIA SYNTHESIS OF BILE ACIDS, DIRECT BILIARY EXCRETION, AND SOME MINOR PATHWAYS THE BALANCE IS SYNTHESISED FROM ACETATE VIA MEVALONATE ETC IN LIVER AND OTHER CELLS CHOLESTEROL FORMS THE STARTING PRODUCT FOR STEROID HORMONES, VITAMIN D WE WORRY ABOUT ITS ACCUMULATION IN FOAM CELLS AND ATHEROSCLEROTIC PLAQUES

WHICH ARE THE NASTY LIPOPROTEINS?

THE EVIDENCE IS OVERWHELMING THAT THE HIGHER THE LDL CHOLESTEROL, THE GREATER THE RISK THERE IS ALSO GOOD EVIDENCE THAT IDL ARE A RISK FACTOR THERE IS ALSO OVERWHELMING EVIDENCE THAT THE HIGHER THE HDL CHOLESTEROL, THE LESS THE RISK BUT THIS APPLIES ONLY TO NATURAL HDL, SOME RECENT DRUG DEVELOPMENTS THAT INCREASE SOME FRACTION OF HDL DO NO GOOD

MEASURE CHOLESTEROL OR APOPROTEINS?

APO-B IS FOUND ON CHYLOMICRONS, VLDL, IDL, LDL. IN FASTING STATE IT IS MAINLY ON IDL AND LDL AS THE OTHER TWO HAVE BEEN USED UP APO-A IS FOUND ON HDL, CHYLOMICRONS AND VLDL AND SO IN FASTING STATE MAINLY ONLY ON HDL SO MEASUREMENT OF APO-A AND APO-B CAN GIVE MUCH THE SAME INFORMATION IN A FASTED PATIENT AS HDL-CHOLESTEROL AND LDLCHOLESTEROL EXPERTS ARE STILL ARGUING WHICH IS BETTER

MEASUREMENT STRATEGY
WE CAN MEASURE TOTAL CHOLESTEROL WELL THERE ARE RELIABLE METHODS WITH APPROPRIATE DETERGENTS AND DIVALENT CATIONS TO MEASURE HDL-CHOLESTEROL IN AN AUTOMATED ONE-STEP PROCEDURE THE AUTOMATED LDL-CHOLESTEROL DIRECT MEASUREMENTS ARE NOT YET OFTEN DONE WE CALCULATE LDL-CHOLESTEROL FROM THE DIFFERENCE BETWEEN TOTAL AND HDLCHOLESTEROL, WITH A CORRECTION FOR VLDL CHOLESTEROL BASED ON PLASMA TRIGLYCERIDE

IS TRIGLYCERIDE A RISK?
EARLY STUDIES CONCENTRATED ON CHOLESTEROL HOWEVER EVIDENCE IS ACCUMULATING THAT HIGH TRIGLYCERIDE LEVELS (>4) REPRESENT AN ADDITIONAL RISK THIS IS PERHAPS A CONSEQUENCE OF THE EXTRA LOAD OF CHOLESTEROL WHICH IS IN THE COATING OF THE EXTRA VLDL AND MUST BE METABOLISED HIGH TRIGLYCERIDES ARE ALSO A RISK FOR PANCREATITIS

SOURCE OF TRIGLYCERIDE
DIETARY FAT AND THE RESULTANT CHYLOMICRONS HAVE A REASONABLY SHORT LIFE IN PLASMA THE MAJOR SOURCE OF PLASMA TRIGLYCERIDE IS VLDL, WHICH HAS A SLOWER TURNOVER THAN CHYLOMICRONS VLDL ARE MADE IN LIVER, FATTY ACIDS COME FROM:
1. FATTY ACIDS TAKEN UP FROM LIPOPROTEIN REMNANTS 2. FATTY ACIDS SYNTHESISED FROM CARBOHYDRATES 3. FATTY ACIDS LIBERATED IN EXCESS FROM ADIPOSE TISSUE BY HORMONE-SENSITIVE LIPASE, WHICH IS STIMULATED BY CATECHOLAMINES, GLUCAGON, STRESS, NICOTINE ETC

THUS LIFESTYLE INTERACTS VIA THESE PATHWAYS TO INCREASE LDL AND RISK

WHO ARE AT HIGHER RISK?

TEXT BOOKS LOVE TO WRITE AT LENGTH ABOUT DISORDERS OF LIPID METABOLISM THAT HAVE A GENETIC BASIS AND ARE ALL RELATIVELY RARE THEY USUALLY OMIT TO GIVE PROPER EMPHASIS TO THE COMMON CAUSES OF DYSLIPIDAEMIA: AS: OBESITY ESPECIALLY COMMENCING IN THE YOUNG AND THEREFORE PRESENT LONGER DIABETES MELLITUS BINGE EATING AND OVER-EATING IN GENERAL EXCESS ALCOHOL INTAKE ? WRONG FATTY ACIDS IN DIET INADEQUATE -3, TRANS-UNSATURATED ETC

GENETIC CAUSES
STUDY OF THESE CAN GIVE US INSIGHTS INTO THE ROLE OF THE VARIOUS PROTEINS, ESPECIALLY IN DIAL-A-MOUSE TYPE STUDIES THE ONLY ONE OF ANY FREQUENCEY IS THE B RECEPTOR DEFECT, WHICH IN THE HETEROZYGOTE RESULTS IN A TOTAL CHOLESTEROL AROUND 8 MMOL/L OR MORE AND EARLY ATHEROSCLEROSIS (30-50 YEARS). IN THE (RARE) HOMOZYGOTE THE CHOLESTEROL IS WELL OVER 10 MMOL/L AND THE SUFFERERS USUALLY DIE IN EARLY CHILDHOOD