How Does This Fat Transport Gene Affect Metabolic & Cardiovascular Disease? (APOA5)

APOA5 encodes a fat transport protein called apolipoprotein A5 (also abbreviated as ApoA5). It is similar in structure to other apolipoproteins, including the well-known APOE; like other proteins of this type, it binds to fat molecules and transports them through the bloodstream [R].

APOA5 specifically forms a part of HDL (high-density lipoprotein), sometimes known as “good cholesterol” [R].

HDL particles help remove excess cholesterol from the blood by [R, R, R]:

• transporting it to the liver, where it becomes a part of bile and is excreted through feces
• taking it to adrenal glands, ovaries, and testes, where cholesterol is converted into steroid hormones (e.g. cortisol, estrogens, testosterone)

Cholesterol transported by HDL is known as “good” cholesterol because it is being removed from artery walls, which helps prevent, reduce, and even reverse hardening of the arteries (atherosclerosis) and heart disease [R].

ApoA5’s Role in Metabolic Disease

ApoA5 has a well-documented link to metabolic diseases and fat levels in the blood. Its mechanism is not completely understood and is believed to be fairly complex. Generally speaking, however, lower apoA5 activity is associated with metabolic disruption [R, R].

ApoA5 binds up fats, and people with higher apoA5 levels may have significantly reduced triglycerides in their blood. This lipoprotein is also believed to regulate how fat is stored, making it an important marker in the study of obesity [R].

This is where it gets a little complicated: when apoA5 binds up fats in the blood, it is also preparing those fats to be stored as fat tissue. People with low apoA5 activity are actually less likely to gain weight on a high fat diet for this reason; however, they are more likely to develop metabolic disruptions and cardiovascular disease, possibly because fats are allowed to circulate in the bloodstream rather than be stored [R, R].

For metabolic health, it is therefore beneficial to have increased apoA5 activity even if it might increase fat deposition on a high-fat diet specifically [R, R].

ApoA5 is a fat-binding protein that reduces blood triglycerides, packages them into HDL cholesterol, and eventually regulates their storage as fat tissue. People with low apoA5 gain less weight from fat-rich diets. However, they have increased rates of metabolic disease.

Multiple variants in the APOA5 gene have been associated with metabolic syndrome, dysregulated fat deposition, and obesity [R].

Each ‘G’ allele of rs662799 is associated with less apoA5 activity, higher blood triglycerides, and increased rates of metabolic disruption, even as this same allele is associated with less weight gain on a high fat diet [R].

At rs651821, the ‘C’ allele is associated with less apoA5 activity and disrupted blood fats. Similarly, the ‘G’ allele of rs964184 and the ‘G’ allele of rs2266788 are associated with less apoA5 activity, decreased HDL, and increased blood triglyceride fats [R, R, R].

The Key to APOA5, HDL & Fat Deposition?

Even though the relationship between apoA5 and obesity is complicated, your APOA5 gene may provide important information about the best weight management strategies for you.

If you have high APOA5 expression, you may expect your HDL to be higher, your triglycerides to be lower, and your body to deposit fat normally in response to dietary fat. This is considered normal and healthy fat metabolism. If you fall into this category, you may want to reduce your intake of dietary (especially saturated) fats to prevent weight gain [R, R].

If you have low APOA5 expression, you may expect your HDL to be lower, your triglycerides to be higher, and your body to deposit less fat than normal in response to dietary fat. If you fall into this category, your body may (counter-intuitively) need a little extra help managing your blood fat levels; you may wish to focus on lifestyle and diet strategies that increase HDL cholesterol and reduce blood triglycerides to maximize your metabolic health [R, R].

APOA5 variants that reduce expression are associated with reduced weight gain on a high fat diet, but increased metabolic disruption in the form of low HDL and high blood triglycerides.

SNP Summary and Table

APOA5 rs662799

• ‘A’ = Normal weight gain on high-fat diets, not associated with disruptions to metabolic health
• ‘G’ = Prevents weight gain on high-fat diets but may disrupt metabolic health
• Only about 29% of all people worldwide have at least one copy of the ‘G’ allele.
• The ‘G’ allele is significantly more common in people of East Asian descent (50%) and significantly less common in people of European descent (16%).

APOA5 rs651821

• ‘T’ = Not associated with metabolic disruption
• ‘C’ = Associated with reduced HDL, increased blood fats
• About 31% of all people worldwide have at least one copy of the ‘C’ allele.
• The ‘C’ allele is significantly more common in people of East Asian descent (50%) and significantly less common in people of European descent (15%).

APOA5 rs964184

• ‘C’ = Not associated with metabolic disruption
• ‘G’ = Associated with reduced HDL, increased blood fats
• About 39% of all people worldwide have at least one copy of the ‘G’ allele.
• The ‘G’ allele is more common in people of American descent (48%) and less common in people of European descent (29%).

APOA5 rs2266788

• ‘A’ = Not associated with metabolic disruption
• ‘G’ = Associated with reduced HDL, increased blood fats
• Only about 23% of all people worldwide have at least one copy of the ‘G’ allele.
• The ‘G’ allele is significantly more common in people of East Asian (42%) and South Asian (36%) descent and dramatically less common in people of African descent (1%).