lipoproteins
large macromolecular complexes that transport hydrophobic lipids: TGs, cholesterol, & fat-soluble vitamins (plasma, interstitial fluid & lymph)
function of lipoproteins
- the absorption of dietary cholesterol, long-chain fatty acids & fat-soluble vitamins
- transport TGs, cholesterol, & fat-soluble vitamins from the liver to peripheral tissues & the transport of cholesterol from peripheral tissues to the liver
apolipoproteins
- activate enzymes important in lipoprotein metabolism
- ligands for cell surface receptors
ApoA-I, ApoA-II
HDL
ApoB-48
chylomicrons
intestine
ApoB-100
VLDL, IDL, LDL
liver
ApoE, ApoC
chylomicrons, VLDL, IDL
metabolism & clearance
ApoB does not
transfer between lipoproteins
primary disorders of lipoprotein metabolism
genetic
familial hypercholesterolemia
secondary disorders of lipoprotein metabolism
obesity DM (esp T2) thyroid diseases renal diseases liver diseases alcohol estrogen lysomal storage disease cushing's syndrome drugs
familial hypercholesterolemia
an autosomal codominant disorder characterized by elevated plasma levels of LDL-C with normal TGs, tendon xanthomas & premature coronary atherosclerosis
- large # of LDL receptor mutations
elevated LDL-C in FH are due to
an increase in the production of LDL from IDL& delayed removal of LDL from the blood
TC levels in FH
> 500mg/dL & can be higher than 1000mg/dL in homozygotes
200-400mg/dL in hetero
FH can lead to
- accelerated atherosclerosis, which can result in disability & death in childhood
- symptomatic coronary atherosclerosis before puberty (homo)
- symptoms can be atypical & sudden death is NOT uncommon
FH homozygous diagnosis
- family history
- skin biopsy measuring LDL receptor activity in cultured skin fibroblasts
- flow cytometry analysis of LDL receptor density on lymphocytes
- DNA sequencing to find mutations in LDL receptor gene
obesity
- increased adipose tissue mass
- insulin resistance
- increased FFAs are delivered to the liver from adipose tissue- VLDLs
- high insulin promotes FA synthesis in the liver
- Low HDL-C
secondary alterations in lipid metabolism examples
obesity DM hypothyroidism renal disorders liver disorders alcohol
T1DM
- type 1 usually w/out hyperlipidemia if glycemia is under control
- ketoacidosis–hyperTGs due to increased hepatic FFA influx from adipose tissue
T2DM
- decreased LPL activity
- increased release of FFA from adipose
- increased synthesis of FA in the liver
- increased hepatic production of VLDLs
- elevated levels of TGs from VLDL
- increased LDL
- decreased HDL-C
hypothyroidism
- elevated LDL-C due to a reduction in hepatic LDL receptor function, delaued clearance of LDL
- increased circulating IDL
- some times- mild hyperTG
- all pts presenting with incr. plasma LDL-C, IDL or TGs should be screened for hypothyroidism
nephrotic syndrome
- characterized by significant proteinuria (3.5g/day/1.73m^3BSA)
- hypercholesterolemia or hyperTG; a combination of increased hepatic production & decreased clearance of VLDLs with increased LDL production
end stage renal disease (ESRD)
mild hyperTG (<300mg/dL) due to accumulation of VLDLs and remnant lipoproteins in the circulation
renal transplants
usually have increased lipid levels due to the effect of the drugs required for immunosuppression (cyclosporine & glucocorticoids) & present a difficult management problem since HMG-CoA reductase inhibitors must be used cautiously in these pts
hepatitits
increased VLDLs & mild-moderate hyperTG
- severe hepatitis & liver failure- reduced plasma cholesterol & TGs
