Lipid (Fat) Metabolism: The scientific basics

Saturated fats, trans-fats and omega-6 oils are all over-supplied in modern foods; they should be reduced in your diet. Omega-3 oils are under-consumed and should be increased for your health.

Fat is an indispensable building material for every single cell. It also serves as the primary energy reserve in humans and animals. In the last several decades, overweight and obesity have become epidemics in developed countries due to excessive energy intake and subsequent fat storage. Nevertheless, we cannot live without fat.

The storage and transportation form of fat is called triglyceride. Each triglyceride molecule is composed of one glycerol and three fatty acid molecules. Fatty acids are molecules with a long hydrocarbon chain attached to a carboxyl group. The fatty acids can vary from one triglyceride molecule to another and within one triglyceride molecule depending on their availability. Free fatty acids are also components of cell membranes, precursors for many biologically active molecules, and direct substrates for energy production via the beta oxidation pathway.

Nomenclature of fatty acids

Most natural fatty acids contain even numbers of carbon atoms in straight chains. Commonly accepted nomenclature for fatty acids is the letter ‘C’ followed by total number of carbon atoms and the total number of double bonds separated by a colon. For example, stearic acid is C18:0 (18 carbons, no double bond), arachidonic acid is C20:4 (20 carbons, four double bonds) and docosahexaenoic acid is C22:6 (22 carbons, six double bonds).

Saturated vs. unsaturated fatty acids

Fatty acids can be separated into two types: saturated and unsaturated. Fatty acids without any double bonds between carbon atoms are called saturated fatty acids (SFA). Fatty acids that contain double bonds between carbon atoms are called unsaturated fatty acids. Unsaturated fatty acids are further classified to MUFAs (monounsaturated fatty acids), which have only one double bond, and PUFAs (polyunsaturated fatty acid), which have two or more double bonds. Consumption of SFAs is associated with increased LDL cholesterol and a higher risk for cardiovascular diseases. Consumption of unsaturated fatty acids (regardless of MUFA or PUFA) is associated with decreased LDL cholesterol and a lower risk for cardiovascular diseases.

Omega−3 vs. Omega−6

PUFAs can be further subdivided into two types: omega-3 fatty acids, which are also known as ω-3 fatty acids or n-3 fatty acids in nutrition literature, and omega-6 fatty acids, also known as ω-6 or n-6 fatty acids.

Omega-3 fatty acids are PUFAs with double bonds starting after the third carbon atom from the methyl end of the carbon chain. The most commonly mentioned omega−3 fatty acids in nutrition literature are α-linolenic acid (ALA, C18:3), eicosapentaenoic acid (EPA, C20:5), and docosahexaenoic acid (DHA, C22:6). Omega-3 fatty acids are found in fish oils, algal oil and many plant seeds oils. They provide many health benefits in relation to cardiovascular disease prevention, anti-inflammation and possible anti-cancer functions.

Omega-6 fatty acids are PUFAs with double bonds starting after the sixth carbon atom from the methyl end of the carbon chain. The most common omega-6 fatty acids are linoleic acid (LA, C18:2) and arachidonic acid (AA, C20:4). Linoleic acid is an essential fatty acid for the human body and is abundant in plant oils. Arachidonic acid is not an essential fatty acid because it can be synthesized in the body from linoleic acid. Meat, dairy products, and eggs are the major food sources of arachidonic acid. omega-6 fatty acids play important structural and regulatory roles in a normal cell, but eating too much of them can increase risks for heart attacks, thrombotic stroke, arrhythmia, arthritis, osteoporosis, inflammation, mood disorders, obesity, and cancer. A detailed description of omega-6 vs. omega-3 fatty acids and their impacts on human health is available here.

TABLE 1. COMMON NATURAL FATTY ACIDS IN THE HUMAN DIET

TYPES COMMON NAME STRUCTURE SOURCE
SFA Lauric C12 : 0 coconut fat, palm kernel oil
Myristic acid C14 : 0 milk, coconut fat
Pamitic acid C16 : 0 palm oil, milk, butter, cheese, cocoa butter,
animal meat
Stearic acid C18 : 0 palm oil, milk, butter, cheese, cocoa butter,
animal meat
MUFA Palmitoleic acid C16 : 1 marine animal oil
Oleic acid C18 : 1 olive oil, canola oil, most dietary fat
ω-6 PUFA linoleic acid (LA) C18 : 2 corn oil, soybean oil, sunflower seed oil, peanut oil
Arachidonic acid (AA) C20 : 4 small amount in animal fat
Arachidonic acid (AA) C20 : 4 small amount in animal fat
ω-3 PUFA α-Linolenic acid (ALA) C18 : 3 flaxseed oil
Eicosapentaenoic acid (EPA) C20 : 5 fish oil, marine algae
Docosahexaenoic acid (DHA) C22 : 6 fish oil, marine algae

Essential fatty acids

Essential fatty acids cannot be synthesized by the human body and must come from dietary intake. There are two essential fatty acids for humans: α-linolenic acid (ALA, C18:3, omega-3) and linoleic acid (LA, C18:2, omega-6). Essential fatty acid deficiency can result in retarded growth, dermatitis, kidney diseases and early death.

Trans vs. cis fat

For unsaturated fatty acids, the orientation of the two hydrogen atoms adjacent to a double bond has a major impact on the chemical properties of the molecule. When these two hydrogen atoms are orientated in opposite directions, they are called trans. When they are oriented in the same direction, they are cis. Most naturally occurring unsaturated fatty acids are cis. Trans-fat is rare in natural food sources but is abundant in processed food as a result of the artificial hydrogenation of natural oil. Trans-fat is easier to process but hydrogenation destroys the essential fatty acids which changes the properties of PUFA fat to those characteristic of saturated fatty acids. Trans-fats are considered a health hazard and are banned in some cities in the United States. The most abundant trans-fat is found in artificial butters (margarine).

Fat as an energy reservoir

Excess dietary calories are converted into and stored as fat in the form of triglycerides. When the body requires energy, such as during times of fasting or inadequate calorie intake, stored triglycerides are broken down to three fatty acid chains and one glycerol molecule in a process called lipolysis. The three fatty acids provide energy through a process called the beta oxidation pathway. The major product of the beta oxidation pathway (acetyl-CoA) enters another process called the TCA cycle (tricarboxylic acid cycle, also known as Krebs cycle or the citric acid cycle) to produce even more energy. The glycerol molecule is converted into glucose, and gives cells energy via the glycolysis pathway and TCA cycle. Fatty acids can also be converted into ketone bodies, which refer to three molecules acetone, acetoacetic acid, and beta-hydroxybutyric acid. These molecules are valuable energy sources since they are water-soluble and easily transported across the blood-brain barrier. In the brain, ketone bodies can be readily converted to acetyl-CoA and fed into the Krebs cycle for energy production. During conditions where glucose is limited, the brain can get up to 70% of the energy it needs from ketone bodies.

Dietary fat digestion and absorption by the human body

Dietary triglycerides cannot be absorbed by human cells directly. They must be broken down first through a series of processes that require a family of enzymes called lipases. In the mouth, lingual lipase produced in the salivary glands partially breaks down the triglycerides into fatty acids and diacylglycerols. This digestion is continued in the stomach by gastric lipase and in the small intestine by pancreatic lipase, resulting in a mixture of free fatty acids and monoacylglycerols. This mixture is then absorbed by intestinal enterocytes where it, along with cholesterol and the lipoprotein Apo B48, is assembled into nascent chylomicrons to be released into the bloodstream for transport to other tissues.

Fat transportation

All triglycerides are transported in the form of lipoproteins. Dietary triglycerides are mainly transported in the form of chylomicrons and liver-synthesized triglycerides are mainly transported in the form of VLDL (very low density lipoproteins). Different lipoproteins and their metabolism are described here. NEFAs (non-esterified fatty acids), the equivalent of free fatty acids, are produced in adipose tissue by hormone-sensitive lipase hydrolysis of stored triglycerides. They are then transported to other tissues, including skeletal muscle and hepatocytes (liver cells), by albumin. In hepatocytes, NEFAs can be used for energy production, re-packaged into triglycerides and exported as (VLDL), stored within the liver, or converted to ketone bodies.

Triglycerides biosynthesis

Triglycerides are synthesized in many tissues including the gut, liver, adipose tissue, mammary glands and muscle. The starting substrates for triglyceride biosynthesis are fatty acids and glycerol-3-phosphate, an intermediate of the glycolysis pathway. Free fatty acids are first activated into fatty acyl-CoA by fatty acyl-CoA synthetase. Glycero-3-phosphate is then esterified with one fatty acyl-CoA molecule at its first position, then another at the second position. The enzymes for the first position acylation prefer saturated fatty acids and the second position prefer unsaturated. The enzyme phosphatidate phosphohydrolase then removes the phosphate group at the third position to produce diglyceride. Finally, the free hydroxyl group at the diglyceride is esterified with the third fatty acyl-CoA molecule to form a glyceride molecule. In the gut, fatty acids primarily come from the diet. In the liver, fatty acids are supplied by circulating NEFAs or by de novo fatty acids biosynthesis.

Fatty acids biosynthesis

In humans, de novo fatty acids biosynthesis, also referred to as de novo lipogenesis, occurs primarily in the liver, lactating mammary glands and, to a lesser extent, in the adipose tissue. De novo fatty acids biosynthesis converts excess dietary carbohydrates into triglycerides.

Fatty acids biosynthesis starts from acetyl-CoA which is converted to malonyl-CoA by the addition of CO2. This conversion is catalyzed by the enzyme acetyl-CoA carboxylase and uses biotin as a cofactor. A large multi-enzyme complex, fatty acid synthase (FAS) carries out the chain elongation steps by sequentially adding two carbon units from malonyl-CoA at a time. The final product of this series of reactions is palmitate (C16:0). Palmitate can be incorporated into triglycerides or further elongated by enzymes. The newly synthesized fatty acids can be further desaturated by enzymes such as stearoyl-CoA desaturase (SCD), a delta-9 desaturase that catalyzes the conversion of saturated fatty acids (with preference for stearate and palmitate) to their monounsaturated fatty acid counterparts.

De novo fatty acids synthesis is a complex and highly regulated metabolic pathway. The expression of lipogenic genes encoding key enzymes involved in this pathway are regulated by transcription factors LXRs (liver X receptors), SREBPs (sterol regulatory element-binding proteins), and ChREBP (carbohydrate response element binding protein). These three transcription factors are highly responsive to various diets.

Fat as an energy supply

When fatty acids are needed, they are released from the triglycerides by three enzymes: hormone-sensitive lipase, adipose triacylglycerol lipase, and monoacylglycerol lipase. Free fatty acids are then exported into the plasma as NEFAs for transport to other tissues. The glycerol released is transported to the liver to be metabolized through either glycolysis or gluconeogenesis.

Hormone-sensitive lipase is regulated by insulin, glucagon, norepinephrine, and epinephrine. Glucagon is associated with low blood glucose and epinephrine is associated with increased metabolic demands. In both situations, extra energy is needed so the oxidation of fatty acids is increased to meet that need. Glucagon, norepinephrine, and epinephrine bind to G protein-coupled receptors that activate adenylate cyclase to produce cyclic AMP. As a consequence, cAMP activates protein kinase A, which phosphorylates (and activates) hormone-sensitive lipase. When blood glucose is high, lipolysis is inhibited by insulin, which activates protein phosphatase 2A, which dephosphorylates hormone-sensitive lipase thereby inhibiting its activity. Insulin also activates the enzyme phosphodiesterase, which breaks down cAMP and stops the re-phosphorylation effects of protein kinase A.

Adipose triacylglycerol lipase was discovered relatively recently. It is specific to triglycerides yielding diglycerides and free fatty acids as the main products. It is now believed to be rate limiting for the first step in triglycerides hydrolysis. Regulation of the enzymatic activity is assumed to involve hormonal factors that are still unknown.

The monoacylglycerol lipase is believed to be the rate-limiting enzyme in monoacylglycerol hydrolysis, i.e. the final step in triglyceride catabolism, and is found in the cytoplasm, the plasma membrane, and in lipid droplets. It is specific to monoacylglycerols and has no activity against di- or triglycerides.

References

1. Henneman P, van der Sman-de Beer F, Moghaddam PH, Huijts P, Stalenhoef A, Kastelein J, van Duijn CM, Havekes LM, Frants RR, van Dijk KW and Smelt A (2009). The expression of type III hyperlipoproteinemia: involvement of lipolysis genes. Eur J Hum Genet 17, 620–628. PMID:19034316
2. Simopoulos AP (1999). Essential fatty acids in health and chronic disease. Am J Clin Nutr. 70(3 Suppl):560S-569S. PMID:10479232
3. Strable and Ntambi, 2010. Genetic control of de novo lipogenesis: role in diet-induced obesity. Crit Rev Biochem Mol Biol. 45(3): 199–214. PMID:20218765

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