Understanding the
Pathophysiology of
Hypertriglyceridemia

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Stay Informed Download the Genetic Testing for FCS flyer and CORE Clinical Trials Fact Sheet
Pathophysiology of hypertriglyceridemia
The main TRLs in the blood are chylomicrons and very low density lipoproteins (VLDL)1,4
Intestinal wall
Chylomicrons are synthesized from dietary fats by intestinal enterocytes. They enter the bloodstream through the lymphatic system.14,16
Lymph node
VLDL are made in the liver and secreted directly into the bloodstream4
apoB100
VLDL
apoB48
Chylomicron
Chylomicrons and VLDL transport tryglyceries in the bloodstream.1
In muscle and adipose tissues, endothelial cells express lipoprotein lipase (LPL) on their surface16
LPL
TG lipolysis mediated by LPL usually clears chylomicrons from the bloodstream within 3-4 hours after a meal.1,16 LPL also lipolyzes TGs from VLDL leaving TRL remnant particles, intermediate density lipoproteins (IDL) and small, dense low-density lipoproteins (LDL).1
Fatty acids
TRL remnants
When plasma TG levels are optimal (<~1.2 mmol/L (~100 mg/dL), TRL remnant particles are cleared in the liver and may be undetectable in the blood.1
TRL remnants
When TG levels are moderately elevated (>1.5 mmol/L (~150 mg/dL), there is increased VLDL secretion from the liver and chylomicrons from the small intestines. Furthermore, LPL is often impaired, especially in conditions such as obesity, insulin resistance, or diabetes mellitus. These effects lead to accumulation of TRL remnants in the blood.1
TRL remnants contribute to the initiation and progression of atherosclerotic lesions1
In some cases of extreme HTG, such as in the monogenic familial chylomicronemia syndrome (FCS), clearance of chylomicrons from the bloodstream is impaired leading to chylomicronemia.14
Chylomicron remnant
The main TRLs in the blood are chylomicrons and very low density lipoproteins (VLDL)1,4
Chylomicrons are synthesized from dietary fats by intestinal enterocytes. They enter the bloodstream through the lymphatic system.14,16
VLDL are made in the liver and secreted directly into the bloodstream4
Chylomicrons and VLDL transport tryglyceries in the bloodstream.1
In muscle and adipose tissues, endothelial cells express lipoprotein lipase (LPL) on their surface16
When plasma TG levels are optimal (<~1.2 mmol/L (~100 mg/dL), TRL remnant particles are cleared in the liver and may be undetectable in the blood.1
TG lipolysis mediated by LPL usually clears chylomicrons from the bloodstream within 3-4 hours after a meal.1,16 LPL also lipolyzes TGs from VLDL leaving TRL remnant particles, intermediate density lipoproteins (IDL) and small, dense low-density lipoproteins (LDL).1
TRL remnants contribute to the initiation and progression of atherosclerotic lesions1
In some cases of extreme HTG, such as in the monogenic familial chylomicronemia syndrome (FCS), clearance of chylomicrons from the bloodstream is impaired leading to chylomicronemia.14

Hypertriglyceridemia arises from three possible factors, which vary across individuals1

  • increased triglyceride production
  • altered processing and catabolism of TRLs
  • reduced clearance of TRLs or TRL remnants

Production, catabolism, and clearance of triglyceride-rich lipoproteins and their remnants1,9

Production, catabolism, and clearance of triglyceride-rich lipoproteins and their remnants
Production, catabolism, and clearance of triglyceride-rich lipoproteins and their remnants
Approximate sizes and endothelial permeability of lipoprotein particles
Approximate sizes and endothelial permeability of lipoprotein particles

Pancreatitis and atherogenicity associated with triglyceride-rich lipoproteins

The biologic mechanisms of TRL-related atherosclerosis are not fully understood, but the following simplified model has been proposed on the basis of recent research.1,3,17

Pancreatitis and atherogenicity associated with triglyceride-rich lipoproteins
Pancreatitis and atherogenicity associated with triglyceride-rich lipoproteins

Implications for clinical assessment of ASCVD risk

Current evidence indicates that the primary atherogenic substance in TRL-related atherosclerosis is cholesterol contained within TRL remnants.3,4,9,19

But laboratory measurement of TRL remnant cholesterol is technically difficult and not widely available.19

Fortunately, when non-fasting plasma TG levels are < 5 mmol/L they directly and linearly correlate with TRL remnant cholesterol levels.20

Non-fasting plasma TG levels are considered a surrogate measure of TRL-related ASCVD risk.1,9

Levels of remnant lipoprotein cholesterol as a function of TG levels in men and women from the general population20

Plasma TG levels are a reasonable surrogate for remnant cholesterol when plasma TG levels are borderline normal or moderately elevated.

Levels of remnant lipoprotein cholesterol as a function of TG levels in men and women from the general population
Levels of remnant lipoprotein cholesterol as a function of TG levels in men and women from the general population

There is now consensus that moderately elevated plasma TG level (>1.7 mmol/L; 150 mg/dL) is causally related to clinically relevant increased risk of atherosclerotic cardiovascular disease (ASCVD).1

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    SHOW REFERENCES

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