What are triglycerides?

What Are Triglycerides?

Triglycerides are hydrophobic lipid molecules that serve as the body's primary form of stored energy, making up the core of lipoprotein particles in plasma along with cholesteryl esters. 1

Structure and Composition

• Triglycerides are macromolecular complexes that form part of lipoproteins, which carry various lipids and proteins in plasma 1
• They are hydrophobic molecules that, along with cholesteryl esters, compose the core of lipoprotein particles, which is covered by a unilamellar surface containing amphipathic phospholipids, free cholesterol, and proteins 1
• Hundreds to thousands of triglyceride molecules can be carried in the core of different lipoproteins 1

Metabolism of Triglycerides

Dietary Triglyceride Processing

• After a meal, dietary fat and cholesterol are absorbed into the cells of the small intestine and incorporated into nascent chylomicrons 1
• Newly formed chylomicrons contain 80-95% triglyceride by composition and are secreted into the lymphatic system before entering the bloodstream 1
• In the circulation, chylomicrons acquire apolipoproteins (apo CII, apo CIII, and apo E) which regulate their metabolism 1

Triglyceride Breakdown

• In capillary beds of adipose tissue and muscle, chylomicrons bind to glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) 1
• The enzyme lipoprotein lipase (LPL) hydrolyzes the core triglycerides after activation by apo CII 1
• The resulting free fatty acids can be:
  • Taken up by fat cells and reincorporated into triglycerides for storage 1
  • Used by muscle cells for energy 1

Remnant Processing

• After triglyceride hydrolysis, what remains is a cholesteryl ester and apo E-enriched chylomicron remnant (CMR) 1
• Under normal conditions, these remnants are removed by the liver through binding to LDL receptors, LDL receptor-related proteins, hepatic triglyceride lipase, and cell-surface proteoglycans 1

Clinical Significance

Normal and Abnormal Levels

• The American Heart Association suggests the following classifications for fasting triglyceride levels 1:
  • Optimal: <100 mg/dL
  • Normal: <150 mg/dL
  • Borderline high: 150-199 mg/dL
  • High: 200-499 mg/dL
  • Very high: ≥500 mg/dL

Role in Cardiovascular Disease

• Triglyceride is not directly atherogenic but represents an important biomarker of cardiovascular disease risk because of its association with atherogenic remnant particles and apolipoprotein CIII 1
• Elevated triglyceride levels often appear with low HDL-C and elevated LDL-C (the "atherogenic dyslipidemic triad"), which is associated with the highest cardiovascular disease risk 1
• Triglyceride levels provide unique information as a biomarker of risk, especially when combined with low HDL-C and elevated LDL-C 1

Pancreatitis Risk

• Very high triglyceride levels (>1000 mg/dL) are associated with increased risk for pancreatitis 1
• Familial disorders of triglyceride metabolism may be associated with increased risk for pancreatitis when fasting triglyceride levels exceed 1000 mg/dL 1

Common Causes of Elevated Triglycerides

• Obesity and increased BMI are strongly associated with hypertriglyceridemia 1
• Insulin resistance and metabolic syndrome 1
• Diabetes mellitus, particularly type 2 1
• Genetic disorders such as familial hypertriglyceridemia (FHTG) and familial combined hyperlipidemia (FCHL) 1
• Lipodystrophy syndromes, both genetic and acquired (such as HIV-associated) 1
• Medications, including estrogens, certain antiretrovirals, and some antipsychotics 2

Clinical Management Considerations

• Treatment of elevated triglyceride levels focuses primarily on intensive therapeutic lifestyle changes 1:

  • 5-10% reduction in body weight can lead to a 20% reduction in triglyceride levels 1
  • Reducing added sugars and fructose while increasing unsaturated fat intake may contribute an additional 10-20% reduction 1
  • Elimination of trans fats, restriction of saturated fatty acids, and increasing consumption of marine-based omega-3 products can further optimize triglyceride-lowering efforts 1

• For very high triglyceride levels (≥500 mg/dL), medication therapy may be indicated 2:

  • Fibrates such as gemfibrozil or fenofibrate may be used to reduce risk of pancreatitis 2, 3
  • Fenofibrate works by activating peroxisome proliferator activated receptor α (PPARα), which increases lipolysis and elimination of triglyceride-rich particles 3

Measurement Considerations

• Fasting samples are used to designate borderline high, high, and very high triglyceride levels 1
• Nonfasting triglyceride levels should not be used in the calculation of LDL-C by the Friedewald formula 1
• As triglyceride levels increase, the proportion of triglyceride/cholesteryl ester in VLDL increases, which results in an underestimation of LDL-C based on the Friedewald formula 1