Cholesterol sources, biosynthesis and degradation  diet  only found in animal fat  biosynthesis  primarily synthesized in the liver from acetyl CoA  biosynthesis is inhibited by LDL uptake by the liver  degradation  only occurs in the liver  cholesterol is converted to bile acids

Biosynthesis summary

glycerideglyceride in which the glycerol is esterified with three fatty acids. It is the main constituent of vegetable oil and animal fats.glycerol esterifiedfatty acidsvegetable oil animal fats Triglycerides

Cont…  Triglycerides, as major components of very low density lipoprotein (VLDL) and chylomicrons.very low density lipoprotein chylomicrons  play an important role in metabolism as energy sources and transporters of dietary fat. They contain more than twice as much energy (9 kcal/g) as carbohydrates and proteins.metabolismkcalcarbohydrates proteins

Cont…  In the intestine, triglycerides are split into glycerol and fatty acids (this process is called lipolysis) (with the help of lipases and bile secretions), which are then moved into the cells lining the intestine (absorptive enterocytes).intestinelipolysislipasesbile

Cont…  The triglycerides are rebuilt in the enterocytes from their fragments and packaged together with cholesterol and proteins to form chylomicrons.  These are excreted from the cells and collected by the lymph system and transported to the large vessels near the heart before being mixed into the blood.

Cont…  Various tissues can capture the chylomicrons, releasing the triglycerides to be used as a source of energy.  Fat and liver cells can synthesize and store triglycerides.  When the body requires fatty acids as an energy source, the hormone glucagon signals the breakdown of the triglycerides by hormone-sensitive lipase to release free fatty acids.fatty acidsglucagon

Cont…  As the brain can not utilize fatty acids as an energy source, the glycerol component of triglycerides can be converted into glucose for brain fuel when it is broken down.brainglycerol glucose  Fat cells may also be broken down for that reason, if the brain's needs ever outweigh the body's. HDL is the most helpful in preventing coronary heart disease.???

Triglycerides  Associated with increased risk of CHD events  Link with increased CHD risk is complex  may be related to low HDL levels and highly atherogenic forms of LDL cholesterol  May have accompanying dyslipidaemias  Normal triglyceride levels <200mg/dl (2.3mmol/l)  Very high level of triglycerides (>1000mg/dl, 11.3mmol/l) is associated with increased pancreatitis risk

Reducing triglyceride levels  Moderating the consumption of fats and carbohydrates and aerobic exercise are essential to reducing triglyceride levels.  Omega-3 fatty acids from fish, flax seed oil, or other sources (on the order of 5 grams of omega-3 per day) or Omega-6 fatty acids.Omega-3 fatty acids Omega-6 fatty acids  one or several grams of niacin (mega-dose vitamin B-3) per day and some statins reduce triglyceride levels.niacinstatins

Cont…  Fibrates have been used in some cases as some fibrates can bring down TGs substantially.Fibrates  However they are not used in first line as they can have unpleasant or dangerous side effects.  In one case due to an increase in mortality, clofibrate was withdrawn from the North American market.  Alcohol abuse can cause elevated levels of triglycerides.

Possible Atherogenic Changes Accompanying Hypertriglyceridemia Hypertriglyceridemia Increased chylomicron remnants Small, dense LDL Coagulation changes Increased VLDL cholesterol-rich remnants Low HDL Miller M. Eur Heart J. 1998;19(Suppl H):H18- H22.

Risk of CHD by Triglyceride Level (The Framingham Heart Study) N=5127 Castelli WP. Am J Cardiol. 1992;70: 3H-9H. Relative Risk Triglyceride Level (mg/dL)

Frederickson -WHO classification Type I Type I: incr. chylomicrons, reduced HDL, absence of lipoprotein lipase; deficiency of apo CII (hyperchylomironemia) Type II-A Type II-A: raised LDL; decreased catabolism of LDL (receptor deficiency or polygenic) Type II-B Type II-B: raised VLDL + LDL; often reduced HDL; increased production of VLDL + impaired LDL catabolism

CONT…  Type III  Type III: raised IDL (dysbetalipoproteinemia); abnormal apolipoprotein E; impaired catabolism of IDL; elevated cholesterol and triglycerides (formerly known as broad beta disease)

CONT… Type IV Type IV: raised VLDL; often reduced HDL; impaired VLDL catabolism; dietary indiscretion ( formerly known as hyperprebetalipoproteinemia) Type V Type V: raised chylomicrons + VLDL; reduced HDL; reduced lipoprotein lipase + VLDL hypersecretion (formerly known as mixed lipemia)

Classification of Dyslipidaemias Fredrickson (WHO) Classification LDL – low-density lipoprotein; IDL – intermediate-density lipoprotein; VLDL – very low-density lipoprotein. (High-density lipoprotein (HDL) cholesterol levels are not considered in the Fredrickson classification.) Phenotype I IIa IIb III IV V Lipoprotein elevated Chylomicrons LDL LDL and VLDL IDL VLDL VLDL and chylomicrons Atherogenicity None seen Prevalence Rare Common Intermediate Common Rare Serum cholesterol Normal to Serum triglyceride Normal (Adapted from Yeshurun et al., 1995)