Lipids + CVD

• Blood lipids and CVD


  • Importance as markers for CVD risk
  • Different groups of plasma lipids and their relevance for CVD

  
• Cholesterol metabolism and manipulation


  • Endogenous cholesterol synthesis
  • Importance of dietary cholesterol as exogenous source
  • Relevance of plant sterols

  
• Increased plasma cholesterol


  One of the most important risk factors for CVD

  
• Epidemiology has shown a very strong relationship with total cholesterol and CHD mortality independent of other risk factors

  
• Causal relationship is proven by the fact that intervention studies showing reduction of total and LDL cholesterol (bad) demonstrate a significant reduction in CHD mortality

  
• Shows death rate over plasma conc of cholesterol


  • Red line is cholesterol levels that are too high

  
• Not everybody with high cholesterol will develop CVD and not everyone having CVD has high cholesterol levels

  
• Cholesterol levels


  • Total cholesterol: Healthy adults - 5mmol/l or lower (200 mg/dl - green on graph)
  • Average in the UK: 5.5mmol/l (men) and 5.6 mmol/l (women)

  
• Over 100 year of supporting evidence for raised serum LDL-C and increased CVD risk and mortality
• Consensus from EU Atherosclerosis Society (2017) - Serum LDL causally related to atherosclerotic CVD
• Saturated fatty acids (SFA) raise serum LDL-C

  
• Diet-heart hypothesis - has been questioned
• Based on the assumption that SFA raise LCL-C
• High cholesterol increases atherosclerosis and CHD

  
• Basis for the UK guidelines to reduce SFA intake
• Seven countries study (A Keys et al. 1986) correlating average SFA intakes in population, serum cholesterol levels and CHD mortality

  
• Diet-heart hypothesis


  Decreasing blood cholesterol will decrease cardiovascular disease
• No RCT has shown that replacement of saturated fat with linoleic acid significantly reduces coronary heart disease events or deaths

  
• At population level, high SFA consumption per se is not linked to higher CVD incidence and mortality
• However, replacement of SFA does change CVD risk
• Lipoproteins


  Involved in dietary lipid intake + endogenous lipid synthesis

  
• Lipoprotein nomenclature and composition (simplified)


  • CM= chylomicron
  • VLDL= very low-density lipoprotein
  • IDL= intermediate density lipoprotein
  • LDL= low density lipoprotein
  • HDL= high density lipoprotein
  • Apo = apolipoprotein
  • TG=triglyceride
  • CE= cholesteryl ester

  
• Small particles easily get deposited in arterial walls (increased penetration as well as increased binding to subendothelial matrix (in particular via apoB which distinguishes HDL from the others!))
• ApoB containing lipoproteins are more prone to oxidation
• ApoA-I


  Enables cholesterol transport from peripheral tissues

  
• ApoE


  Ligand to LDL receptor (& Remnant receptor)
• Site of synthesis and transport of fats


  • Exogenous pathway: fats consumed
  • Endogenous pathway: Liver synthesises fats + CHOL

  
• Lipoprotein recovery - LDL Receptor (apoB-E receptor)


  1. Remnants of lipoproteins (CR, LDL) are recovered by the liver

  2. Uptake of cholesterol in liver cells – protein facilitated

  3. LDL receptors are regulated by free cholesterol within cells

  4. Increase in LDL receptors on membrane reduces plasma LDL concentrations

  
• HMG-CoA reductase


  Key enzyme in cholesterol synthesis in our body

  
• ACAT enzyme


  Acetyl-coenzyme A cholesterol acyltransferase - Esterification of cholesterol, esterified cholesterol is stored in fat droplets in cytoplasm and therefore limiting the amount of free cholesterol

  
• Familial Hypercholesterolemia


  • Autosomal dominant mutation in LDL receptor (heterozygote: 1 in 500, homozygote: 1 in a Million)
  • Heterozygotes show increased plasma cholesterol with first heart attack at 30-40 years old (50% LDL deficiency causes 2x higher plasma cholesterol)
  • Homozygotes show increased cholesterol and VLDL, with increased risk of cardiovascular disease/obesity (6-10 fold increased LDL Chol)
  • Undiagnosed – Males can have first heart attack at ~2years (females protected for ~20years old) – depends on severity of mutation (partial/total)
  • Men are more affected than women

  
• Role of cholesterol


  • An important component of lipoproteins
  • A fundamental component of cell membranes
  • A precursor of bile acids, steroid hormones (derivatives of CHOL), and vitamin D (activated by UV)

  
• Only found in animal foods, no cholesterol in fruit, legumes etc.
• Sources of cholesterol


  • Diet
  • De novo synthesis

  
• Human body produces around 75% of the cholesterol required – in the liver

  
• The amount of cholesterol gained through the diet is around 25%

  
• Dietary cholesterol intake approx. 200-300mg/day (150-250mg cholesterol per egg yolk)

  
• Assumption: If intake is high, body correspondingly decreases cholesterol synthesis in liver

  
• At lower intake levels linear and above 300-400mg/day – hyperbolic response
• For every 100mg increase – rise of 10mg/dL