Lipid transport

Lipid transport

1. lipids

2. fat deposition

   • subcutaneous
   • visceral
   • bone marrow
   • adipose: white/brown
     • produce leptin + resistin
       • resistin; type 2 + high LDL aka. ADSF

3. Lipogenesis

   • @cytoplasm of adipocyte/hepatocyte
   • insulin stimulates FA synthase expression
     • multi enzymatic system
   • ACP carries sub between active sites

4. Bile salts

   • synthesised @liver
   • stored + concentrated in gall bladder
   • released: S.I
   • amphiphilic
   • ^SA to aid lipase digestion
   • glycocholate

5. fat globule> emulsification > lipases> FFA + bile salts> miscelles> protein + TG> cholymicrons > secretory vesicle> lacteal

6. lipoprotiens

   • lipid core (TAG, Chol esters) fat sol vits, outer monolayer; phospholipid, chol, apolipoprotiens
   • transport mols for chol, fat, ADEK from blood >tissues
   • classes
     • ^ the protein:lipid =^ density
     • CM remnant
       • endocytosis @liver, recog by apo-E component
         • lipases removes TGS: ab by Intestine, assembled in mucose, exretion into plasma by lymphatic system > tissues TG hydrolysed by apo CII dep. activation of lipoprotein lipase on the endothelial cell walls
     • VLDL
       • Assembled@ liver, lipase removes TGs
     • IDL
       • derived TG depletion of VLDL, taken up by liver/depleted further of TGS + become LDL
     • LDL +HDL
       • trsanport dietary + endogenous chol in plasma
       • LDL main transporter of chol + esters in plasma, 50% total lpp in plasma
         • LDL ab @liver - receptor mediated endocytosis
       • HDL
         • Protien rich @liver + intestines, circulating source of apo CI + II + apo E protiens
         • can return to liver where chol is removed
     • Accumulate cholesterol esters, can accumulate from cell membranes and can transfer esters to VLDL and LDL via transferase activity

7. apolipoprotiens

   • recognition sites
   • activators/coenzymes
   • solubilise lipids
   • efficient transport system

8. reverse chol transport

   • uptake chol from peripheral tissues
     • binding by apo-A-I
   • esterification of HDL-C by LCAT activated by apoAI
     • transfer CE> to lipoprotein remnants by CEPT
       • Remove CE rich remnants by liver>bile acids + excreted

9. dyslipidemia

   • disorders of lipoprotein metabolism- overproduction and deficeincy
     • manifests: ^ TC, LDL +TG decreased HDL
   • primary; not due to underlyin g disease- genes
     • secondary; manifestation of disease
     • classification; Fredrickson/WHO : widely accepted plasma analysis

10. TG: 88.6

    • TC LDL HDL: 38.7

11. common Hypercholesterolaemia

    • middle aged
    • top 5% blood chol
    • polygenic
    • diet
    • type IIA
      • most common inherited
      • autosomal dominant
        • 1/500 heterozygotes
      • 1/10000 homo
        • severe disease, <16mmol/l, deposition of chol in arterial walls + skin, tendon xanthomata, xantheplasma, premature arcus senilis, death from CV disease <20yrs.
      • 95% defect is in LDL receptor
        • 5% defect in uptake of LDL
          • apo-B to LDL binding + internalising
            • inability= internalise p's = ^ synthesis by liver
              • decrease clearance of LDL + ^ chol synthesis = chol plasma levels ^
                • ^risk of atherosclerosis + HD
                  • heteroz= 50% men haveCHD/MI by 55%
                    • less severe, 8mmol/l, physical signs less common risk prem death from cv diseas
    • screening
      • detect @ >50
        • if found offered to family

12. hyperlipidaemia- condition management

    • diet
      • low chol + sat fat
        • PolyUs= 9cals/g (N-3, N-6 PUFAS)
      • replace sat with PUFA= lower VLDL + LDL
        • does liver concert FA-> ketone bodies instead of VLDL TGs
          • PUFAS metabolised without leaving a trail of lipoprotiens
      • plant sterols/phytosterols bind chol + reduce ab. from gut
      • nitrates
        • rhubarb, spinach, beets, salad, broccoli, potato, basil
          • provide additional source
        • Nitric oxide produced from arginine by NO synthase
          • NO =vasodilator
      • oats
        • sol fiber- beta-glucan
          • lower ldl
            • fruit, veg, lentils, pulses
              • fibre: gel- binds chol + prevents ab.
    • risk factors management
    • drug therapy to normalise blood lipids
      • most chol is synthesised, inhibition of chol biosynthesis= greater impact on blood lipid conc. than dietary intervention
      • statins: inhibit chol synthesis
        • cells compensate by ^ ldl receptor synthesis= ^ chol uptake + decreased blood chol, reduced inflammation -atherosclerosis
        • HMG-CoA (3hydroxy-3methylglutaryl CoA) reductase inhibitors
        • anti-hyperlipidaemic drugs- competitive binding
        • side effects: muscle pain + cramp, GI disturbance, elevated liver enzymes, Rhabdomyolysis
      • Cholesterol binding resins
        • bind chol in GI tract + reduce chol ab.
          • resins; medications that bind with bile acids. preventing the intestines from recycling them
            • decrease In bile= liver produces more + pulls chol from the blood
        • constipation
      • nicotinic acid
        • decreases VLDL production @liver + LDL
          • ^lipoprotienlipase activity, decrease TG conc
        • admin large doses:0.5-6g d
          • reduced TG + TC
        • ^Bilary secretion of chol, not bile
        • type IIA, IIB, III, IV, V

13. Type IIB: familial combined hyperlipidaemia

    • Fibrates: activate LPL and therefore lower plasma triglycerides
      • supress cholesterol synthesis
    • autosomal dominant
      • 1/300 HTZ
      • + apo-B
    • HMG-CoA reductase defect
    • ^ VLDL secretion from liver leads to ^ plasma LDL
    • raised plasma chol + triglycerides
    • xanthelasma, prem arcus senilis, risk prem death from CVD

14. Familial Hypertriglyceridaemia

    • incidence: 1/500
    • autosomal dominant
    • defect in production/catabolism of VLDL (plasma conc. ^)
    • aise TG chol ormal
    • disease exists in severe mild form
      • severe: obesity/alcohol consumpmtion/diabetes
        • eruptive xanthoma

15. remnant hyperlipoprotienemia

    • rare, abnormal apo-E
    • ^ IDL (VDL remnants)

16. exercise

    • deaths
      • rare, highly publicised, 35yrs+, arrhythmia caused by existing athersclerosis
        • <35: hypertrophic cardiomyopathy, congenital cornoral artery abnormalties/myocarditis
    • blood lipids
      • Aerobic training: decrease in ldl chol + TG
      • no evidence for benefits 3x+ weekly or resistance exercise training
      • caution drawing conclusions as heterogeneity in trials included,

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