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Gene, Diet, Disease

LPL and Triglycerides Metabolism

Three common LPL gene variants are associated with higher triglycerides and lower HDL levels in blood, which can be reduced by low-saturated-fat diet and calorie restriction.

LPL (Lipoprotein lipase) is an enzyme responsible for releasing free fatty acids from their transportation form to the target tissue. As mentioned in Fat Metabolism 101, fatty acids are stored and transported in the form of triglycerides (TG). TG cannot cross cell membrane. To reach the target cells for building materials or for energy supply, TGs have to be packed into specialized complexes called lipoproteins and delivered via blood circulation. At the target tissue, these specialized lipoproteins are captured and hydrolyzed by the LPL enzyme localized on the blood vessel surface. The free fatty acids are then released and absorbed by the target cells (Fig. 1).

Figure 1. The role of LPL on fatty acids releasing from triglycerides (TG) in lipoproteins VLDL and chylomicrons. VLDLs (very low density lipoproteins) are the lipoproteins synthesized in the liver.  Chylomicrons are the lipoproteins formed in the gut from dietary fat. Both VLDLs and chylomicrons are often referred to as TG-rich lipoproteins since the major components of them are triglycerides. In blood circulation, the TG-rich lipoproteins are hydrolyzed by the LPL enzyme localized on the surface of the blood vessel in the target tissue. The free fatty acids released are taken up by the target cells. The TG content in VLDLs and chylomicrons decreases and the TG-rich lipoproteins are getting smaller and denser.  Gradually, VLDL is converted to LDL and chylomicron is converted to chylomicron remnant (CMr). LDL and CMr are then taken up by the liver for recycling, making new VLDL or high-density lipoproteins (HDL).

Many mutations that decrease LPL activity cause lipoprotein lipase deficiency or familial combined hyperlipidemia as the result of TG-rich lipoprotein accumulation. Patients with these diseases are unable to handle a normal meal because high TG in their blood can lead to acute pancreatitis.  However, the distributions of these mutations in human population are relatively rare. Clinical diet and medication are needed to control the symptoms.

Three common LPL gene variations, including the gain-of-function mutation S477X and two restriction fragment length polymorphism (RFLP) Pvu II and Hind III, affect the LPL activity mildly and their influence on blood TG and HDL levels are manageable through dietary interactions. The homozygous major allele genotypes, distributed at 74%, 47% and 29% respectively in human population, are the risk genotypes associated with increased TG and decreased HDL levels in response to modern Western diet (Table 1).

Table 1. Allele and genotype frequency of three common LPL gene polymorphisms in general population. The allele distributions of these three polymorphisms do not show significant difference between ethnic groups.

Polymorphisms SNP# Allele (frequency %) Genotype (frequency %)
Minor Major Minor/Minor Minor/Major Major/Major (risk genotype)
S447X rs328 X (10%) S (90%) X/X (2%) X/S (24%) S/S (74%)
Hind III rs320 H- (29%) H+ (71%) H-/H- (10%) H-/H+ (43%) H+/H+ (47%)
Pvu II rs285 P- (46%) P+ (54%) P-/P- (25%) P-/P+ (46%) P+/P+ (29%)

LPL activities in the risk genotypes are lower than that in the minor allele carriers. Lower LPL activity, hence a less ability to clear TG-rich lipoproteins in blood circulation, leads to increased TG levels.  Furthermore, the accumulation of TG-rich lipoproteins leads to more TG being transferred to HDL, turning “the good cholesterol” HDL into “the bad cholesterol” LDL-like particles (Fig. 1).  Therefore, lower LPL activity also results in lower HDL levels. High TG and lower HDL are both risk factors for cardiovascular diseases.  Indeed, all three risk genotypes are associated with higher risks for cardiovascular diseases than the minor allele carriers.

The lower LPL activity means the risk genotype carriers cannot handle high-saturated-fat diet well.  Their TG levels increase and HDL level decrease more than the minor allele carriers in respond to high-saturated-fat diet.  Therefore, they are better off with diets containing minimal amount of saturated fat. The risk genotype carriers also have unfavorable response to excess energy intake, which normally lead to fat synthesis in the liver and increased TG-rich lipoproteins in the blood circulation. On the other hand, calorie restriction limits the amount of fat synthesis and decreases the TG-rich lipoproteins in blood. Therefore, calorie restriction shows a greater improvement to the lipid profile of the risk genotype carriers.

In addition to dietary components, these three LPL variants also interact with niacin (vitamin B3), lifestyle, exercise and medicine differentially. In short, the risk genotypes respond to inadequate amount of dietary niacin, sedative lifestyle, smoking and endurance exercise unfavorably than the minor allele carriers.  However, they are better responders to the insulin sensitizing drug pioglitazone.

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