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HDL

May be cardioprotective through the following mechanisms:

1) Reverse cholesterol transport

2) Inhibition of LDL oxidation

3) Reduction in levels of adhesion proteins

4) Increased fibrinolysis

Genetic disorders characterized by low HDL concentrations are rare and include:

1) mutations in ApoA1

  • Chroni A. 2005. Point mutations in ApoA1 mimic the phenotype observed in patients with classical lecithin:cholesterol acyltransferase deficiency. Biochemistry. 44:14353-66.

2) defects in HDL-mediated efflux of cholesterol from peripheral cells through the membrane transporter ABCA1.

  • Albrecht C. 2004. Two novel missense mutations in ABCA1 results in altered trafficking and cause severe autosomal recessive HDL deficiency. Biochim Biophys Acta. 1689:47-57.

3) hypercatabolism of normal ApoA1.

  • Emmerich J. 1993. Familial HDL deficiency due to marked hypercatabolism of normal ApoA1. Arterioscler Thromb. 13: 1299-306.

The majority of low HDL levels is due to lifestyle factors including obesity, physical inactivity, diet, smoking, and advanced alcholol-related liver disease.

  • Williams PT. 1995. Metab Clin Exp. 44:106-14
  • Diehl AK. 1988. Atherosclerosis. 69: 145-53.
  • von Eckardstein A. 2001. Curr Opin Lipidol. 11:627-37.

Low levels of HDL-cholesterol is considered <35  mg/dL.

  • Rader DJ. J Clin Invest. 2006; 116: 3090-100.

Cardioprotection increases with each 1 mg/dL elevation in HDL and reduces CVD risk by 2-3%, independent of LDL and TG.

  • Toth PP. 2005. Am J Cardiol. 96:50K-8K.

Plasma HDL and ApoA1 levels are negatively associated with increasing BMI. BMI shows stronger negative association with HDL than other CVD risk factors such as LDL.

  • Lamon-Fava S. 1996. Arterioscler Thromb Vasc Biol. 16:1509-15.

Close correlation between intra-abdominal fat and indicies of CVD including low HDL/ total cholesterol ratio, hypertension, glucose tolerance, hyperTG, hyperINS.  15% of variation in HDL/total cholesterol ratio was explained by visceral fat mass (VAT).

  • Peris AN. 1989. Ann Intern Med. 110:867-72.
  • Despres JP. 1989. Arteriosclerosis. 9:203-10.

Ethnic/ racial differences are consistent with effects of VAT on HDL levels.  Lower VAT in black vs whites was correlated with elevated plasma HDL levels.

  • Despres JP. 2000. Arterioscler Thromb Vasc Biol. 20:1932-8.

The knowledge that HDL levels are important markers of CVD risk and that low HDL levels are associatied with adiposity has stimulated research on the mechanisms of how obesity can lower HDL.

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Free fatty acid production

Occurs through insulin resistance.

VLDL production

VLDL2 largely arises from VLDL11,2, although some is produced in the liver, dependent on cholesterol synthesis, cholesterol ester availability and microsomal transfer protein activity.

References
1Packard, C. J., A. Gaw, T. Demant, and J. Shepherd. 1995. Development and application of a multicompartmental model to study very low density lipoprotein subfraction metabolism.J. Lipid Res.36:172–187.

2Stalenhoef, A. F., M. J. Malloy, J. P. Kane, and R. J. Havel. 1984. Metabolism of apolipoproteins B-48 and B-100 of triglyceriderich
lipoproteins in normal and lipoprotein lipase-deficient humans. Proc. Natl. Acad. Sci. USA. 81: 1839–1843.

Storage of endogenous fat

VLDL is secreted from the liver, dependent on the action of ApoB-100. The VLDL is broken down: the TG is hydrolyzed into free fatty acids and glycerol by lipoprotein lipase + ApoC-II, leaving VLDL remnants.

VLDL remnants are ultimately broken down into IDL. IDL is either removed through the combined action of ApoE with the LDL receptor OR the TG in IDL is hydrolyzed by hepatic lipase to produce LDL.

LDL is removed by ApoB-100 and the LDL receptor. If it is not, and is oxidized, it can become part of a macrophage.

Causes of atherosclerosis

Delayed / incomplete removal of chylomicrons

 

The storage of dietary fat

Dietary fat is secreted on chylomicrons. The chylomicron is broken down: the TG is hydrolyzed into free fatty acids and glycerol by lipoprotein lipase + ApoC-II, leaving a chylomicron remnant.  The remnant is removed by the LDL-like receptor protein.