Metabolics and Fat Metabolism

Fat Metabolism

Fats are an essential energy source and have structural, metabolic and immune functions. They impact brain development and cognitive function, cardiovascular health and inflammation, and help absorption of fat-soluble vitamins (A, D, E and K).
There are four major types of dietary fats: saturated fats, trans fats, monounsaturated fats and polyunsaturated fats.

Saturated fats are made up of carbon chains that are all bonded (saturated) with hydrogen. They are mainly found in animal sources, such as meat, butter and cheese, and some plant sources such as coconut oil. Historically, saturated fats have been considered as detrimental to health as their overconsumption is one of the leading causes of obesity.

Unsaturated fats have spaces along the chain of carbon atoms, instead of being saturated with hydrogen. Monounsaturated fats (MUFAs) contain one unsaturated bond. As they help to increase 'good' cholesterol and lower 'bad' cholesterol, MUFAs are considered healthy. Examples include olives, avocados and pumpkin seeds.
Polyunsaturated fats (PUFAs) contain more than one double bond in their carbon chain. They include omega-3 and omega-6 fatty acids, which are essential as the body can't produce them. They are found in a variety of animal and plant-based sources – oily fish, nuts and vegetable oils.

Trans fats are a type of unsaturated fat that has been hydrogenated. Although trans fats occur naturally (in milk, for example) the majority, including hydrogenated vegetable oil, margarine and baked goods (olive oil spreads, crisps, biscuits, cakes and pizzas), are manufactured. Trans fats are considered the worst fats to consume as a diet high in these fats increases the risk of heart disease.

Circulating Fats

Triglycerides are the most common form of dietary fats. As they are not water-soluble, triglycerides and cholesterol are packaged as lipoproteins for transport to target tissues and cells. There are different types and functions of lipoproteins such as chylomicrons, VLDL (very- low-density lipoprotein), LDL (low-density lipoprotein) and HDL (high-density lipoprotein). LDL is considered a 'bad' cholesterol as it contributes to fat buildups in arteries (atherosclerosis) as opposed to HDL being considered 'good'.

Lipoprotein lipase coded by the LPL gene is located on the surface of the cells. LPL breaks down triglycerides in lipoproteins to free fatty acids (FFAs) which can then be taken up by muscle cells or adipocytes for energy production or storage. Once emptied of triglycerides, the lipoproteins evolve to become HDL. A SNP on LPL is associated with increased activity – lower triglyceride levels, higher HDL and reduced risk of coronary artery disease. Exercise (especially aerobic), lipid-lowering agents and statins can also promote LPL activity.

Fatty acid transport proteins (FATPs) and CD36 (also called FAT) facilitate the uptake of FFAs into adipocytes and muscle cells. CD36 is the free fatty acid equivalent of the GLUT transporters (for glucose). It also impacts taste and dietary fat perception. Reduced CD36 sensitivity due to genetic variance is associated with a greater liking for high-fat foods and increased risk of visceral obesity.

Although carbohydrates are the cell's favoured fuel source, this order can be disrupted by fatty acid binding protein (FABP2). A SNP on FABP2 increases activity, preferentially moving fats into the cell, and crowding out glucose. This increases the risk of insulin resistance, hyperinsulinemia, and type 2 diabetes. SNP carriers benefit from limiting intake of saturated fats. Polyphenols, especially carnosic acid found in rosemary and sage, can inhibit FABP2 activity.

Cellular Fats

When fatty acids enter the cell, they can either be directly used for energy production or be stored as triglycerides (fat droplets).

When glucose levels are low, the body uses fat as an alternative energy source. Lipolysis is the process through which lipases break down triglycerides to their constituent molecules – FFAs and glycerol. PPARA (peroxisome proliferator-activated receptor alpha) is activated when energy levels are low and initiates fat metabolism. A SNP is associated with lower activity and is less compatible with a ketogenic diet. Resveratrol, isoflavones, flavonoids and PUFAs can increase PPARA function.

Several genes are involved in regulation of lipolysis including PLIN1 (perilipin 1) and ADRB3 (adrenaline receptor beta 3). PLIN1 controls access to adipocyte triglycerides and protects them from being broken down by lipases. A SNP on PLIN1 is associated with lower expression, higher rates of lipolysis and less risk of obesity. However, it can also confer resistance to weight loss on an energy-restricted diet. Conversely, ADRB3 induces fat break-down by stimulating lipases. A SNP confers reduced sensitivity to adrenaline, slower lipolysis and oxidation, and increased fat accumulation. Carriers of this SNP might also experience resistance to weight loss in response to lifestyle interventions combining diet and exercise. In this case, adrenaline, caffeine, water, fasting, cold exposure, high intensity exercise, bananas, chocolate and green tea can induce lipolysis.

FFAs are converted to acyl-CoA, which is transported across the mitochondrial membrane by CPT1A (carnitine palmitoyltransferase 1A). When glucose is present, malonyl-CoA restricts acyl-CoA (and carnitine) from entering the mitochondria. However, in a low glucose state AMPK lowers malonyl-CoA, enabling entry. Acyl-CoA then undergoes beta-oxidation to produce acetyl- CoA. After beta-oxidation, acetyl-CoA enters the Krebs cycle to produce ATP.

A SNP on CPT1A results in a decreased activity and transport of fatty acids into the mitochondria. This can cause multiple symptoms such as fatigue, dizziness, abdominal pain, muscle pain or weakness, low blood sugar, and low ketone levels (especially during fasting or illness). A high-fat (ketogenic) diet is not advised for carriers of this SNP as it is more likely that fat will be stored rather than burned. Avoid skipping meals, exposure to cold, stress and strenuous exercise. Medium chain triglyceride (MCT) oil and L-carnitine supplementation may be helpful. Conversely, individuals with CPT1A wild genotype are likely to benefit from a ketogenic diet.

Ketogenesis is an alternative pathway which produces ketone bodies. It produces energy for the brain, heart and skeletal muscle during low glucose states such as fasting, prolonged physical activity and sleep. A ketogenic diet can have many health benefits such as weight loss, improved blood sugar, improved metabolic profile and heart health. Alcohol is a potent inhibitor.

Lipogenesis is the opposite of lipolysis, converting acetyl-CoA back to fat for storage. It is upregulated by insulin, glucose, and high energy state and downregulated by leptin. SREBF1 (sterol regulatory element-binding factor 1) activates lipogenic genes and some glycolytic ones too (GCK). It facilitates the storage of excess fatty acids as triglycerides and promotes cholesterol synthesis. Both low and high activity of SREBF1 contribute to insulin resistance and type 2 diabetes. A SNP on this gene is associated with higher SREBF1 expression, higher LDL and total cholesterol and increased risk of type 2 diabetes and non-alcoholic fatty liver disease. SREBF1 is downregulated by high cholesterol and PUFAs.

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