Prescription Omega-3 Fatty Acids and Their Lipid Effects: Physiologic Mechanisms of Action and Clinical Implications

Harold E Bays; Ann P Tighe; Richard Sadovsky; Michael H Davidson


Expert Rev Cardiovasc Ther. 2008;6(3):391-409. 

In This Article

Pathophysiology of Hypertriglyceridemia

Lipoproteins serve to transport varying types and varying amounts of lipids in the circulation, including TG, cholesterol and phospholipids ( Table 2 ).[29] The TGs found in lipoproteins are derived from dietary consumption, intestinal secretion and hepatic production.[29] The term 'triglyceride-rich lipoproteins' (TRLs) most often refers to chylomicrons, VLDL and their remnants. Intermediate-density lipoproteins (IDLs) are often considered to represent VLDL remnants ( Table 2 ).[30,31]

Chylomicron particles deliver lipids derived from dietary fat consumption and intestinal absorption to peripheral and hepatic tissues. VLDL particles transport lipids from the liver to peripheral tissues.[29,31] The enzyme LPL, located on the endothelial side of capillaries within fat and muscle tissue, hydrolyzes TG from both chylomicrons and VLDL into free fatty acids, resulting in the formation of chylomicron and VLDL remnants, respectively.[29,31] These remnants may be atherogenic.[32,33] Mutations in the LPL gene may impair lipolysis from these TRL and significantly increase TG levels; such mutations have been identified in patients with hyper-tri-glyceridemia-induced pancreatitis.[34,35]

Hyperchylomicronemia may occur due to rare genetic defects, resulting in postprandial hyper-tri-glycerid-emia, as has already been described. VLDL excess may also be due to genetic defects (see "Examples of Factors Contributing to Hypertriglyceridemia"). Beyond rare genetic defects, over-production of VLDL may have varying etiologies resulting in fasting hyper-tri-glycerid-emia. For example, adipose tissue is the major energy storage organ of the body, with calories predominantly stored in the form of TG. During times of positive caloric balance, adipo-cytes may become excessively enlarged and visceral adiposity may accumulate, resulting in pathologic adipocyte and adipose tissue dysfunction. Physio-logically, this adiposopathy results in adverse metabolic and immune consequences resulting in the onset or worsening of clinical metabolic diseases, such as Type 2 diabetes mellitus, hypertension and dyslipidemia (Figure 1).[36,37] Thus, clinically, excessive and pathogenic adipocyte hyper-trophy and an increase in visceral adipose tissue (central obesity) are often associated with hyperglycemia, high blood pressure and hyper-tri-glycerid-emia (and low HDL-C levels), which represents a clustering of atherogenic risk factors often described as representing a 'metabolic syndrome'.[1]

Relationship between adiposopathy (pathogenic adipose tissue) and metabolic disease. Increased circulating FFAs may be lipotoxic to muscle, liver and pancreas. When adipocytes become excessively enlarged, especially in the setting of visceral adiposity, adipocyte and adipose tissue dysfunction (i.e., 'adiposopathy') may result in adverse metabolic consequences. One of the manifestations of adiposopathy is a relative increase of intra-adipocyte lipolysis over that of intra-adipocyte lipogenesis, leading to a net release of FFAs, insulin resistance and diminished pancreatic insulin secretion, all leading to hyperglycemia and possible diabetes mellitus, as well as other metabolic diseases. Steatosis, or 'fatty liver', is another consequence of increased FFA delivery to the liver. FFA: Free faty acid. Adapted with permission from Future Medicine Ltd.[7]

One of the metabolic manifestations of adiposopathy is a relative increase of intra-adipocyte lipolysis over that of intra-adipo-cyte lipogenesis, leading to a net release of free fatty acids that may be 'lipotoxic' to body organs.[37] In addition to contributing to the before-mentioned metabolic diseases, increased circulating free fatty acids may also contribute to hepatic steatosis,[38,39] which is a common clinical finding among patients with the components of the m-etabolic syndrome.

With specific regard to TGs, the increase in free fatty acid delivery to the liver increases TG synthesis,[40] which can lead to VLDL overproduction.[41] Increased VLDL production is exacerbated if hepatic free fatty acid ß-oxidation (metabolism) is impaired (e.g., through genetic limitations or with insulin resistance), thereby leaving more substrate for VLDL synthesis. Nonetheless, it is unknown if the increase in the hepatic cytoplasmic TG pool is truly rate-limiting for VLDL-TG or apoB-100 production.[41] However, once hepatocyte TGs are packaged into VLDL particles, they are then secreted into the circulation.[42] Fasting hyper-tri-glycerid-emia ensues, which may also be exacerbated if LPL-mediated lipolysis is impaired and/or the removal of remnant VLDL particles is delayed.[43]

In summary, severe hypertriglyceridemia occurs with increased chylomicrons, VLDL particles and/or their remnants, with causality and promotion being due to primary and secondary factors.[44,45] Primary causes include genetic defects (see "Examples of Factors Contributing to Hypertriglyceridemia"),[15,16,46,47,48,49,50,51] while common secondary contributors that may cause or exacerbate hypertriglyceridemia include pathogenic adipose tissue (visceral adiposity and adipocyte hyper-trophy), excessive and acute consumption of alcohol, consumption of high-glycemic index carbohydrates,[29,52] hyper-glycemia, hypothyroidism and nephrotic syndrome.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.