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Gene, Nutrition, Disease
Common Chronic Disease
Sciences 101
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Fat Metabolism 101
Fat, enjoy it or loathe it, is an indispensible class of building material for every single cell. Beside the function as a component of cell membranes, fat serves the energy reserve for human as well as other animals. Only in the last several decades, due to excess energy intake, excessive fat storage and associated overweight and obesity become an epidemic in the developed countries. Nevertheless, we cannot live without fat.
The storage and transportation form of fat in human body, as well as dietary fat, is called triglycerides. Each triglyceride molecule is composed of one glycerol and three fatty acids molecules. Fatty acids are molecules with a long hydrocarbon chain attached to a carboxyl group. The fatty acids in one triglyceride molecule or in different triglycerides molecules may be different or the same depending on the availability of the free fatty acids during triglycerides synthesis. As the functional mode of fat, free fatty acids are components of the membrane systems in a cell, precursors for many biologically active molecules, and direct substrates for energy production via the beta oxidation pathway.
Nomenclature of fatty acids
Most natural occurring fatty acids contain even numbers of carbon atoms in straight chains. A frequently adopted nomenclature for fatty acids is the total number of carbon atoms following the letter C and the total number of double bond following a colon. For example, stearic acid is C18:0 (18 carbon, no double bound), arachidonic C20:4 (20 carbon, four double bonds) and docosahexaenoic acids C22:6 (22 carbon, six double bonds) etc.
Saturated vs. unsaturated fatty acids
Fatty acids are different from each other in two structural features: the number of the carbon atoms and the number of double bond (C=C) between the carbon atoms. Fatty acids without any double bond are referred to as saturated fatty acids (SFA), with one or more double bounds are called unsaturated. Unsaturated fatty acids are further classified to MUFAs (monounsaturated fatty acids) which have only one double bound, and PUFAs (polyunsaturated fatty acid) which have two or more double bunds. Consumption of SFA is positively correlated with increased LDL cholesterol and higher risk of cardiovascular diseases. Consumption of unsaturated fatty acids (regardless of MUFA or PUFA) is positively correlated with decreased LDL cholesterol and lower risk of cardiovascular diseases.
ω−3 vs. ω−6
From the nutrition point of view, it is important to distinguish two types of PUSFs. One type is the w-3 fatty acids, which are also known as omega-3 fatty acids or n−3 fatty acids in literature. The other type is the w-6 fatty acids, also known as omega-6 or n-6 fatty acids.
The ω−3 fatty acids are PUFAs with a double bond starting after the third carbon atom from the methyl end of the carbon chain. The most common ω−3 fatty acids in nutrition literature include α-linolenic acid (ALA, C18:3), eicosapentaenoic acid (EPA, C20:5), and docosahexaenoic acid (DHA, C22:6), all of which are fund in fish oils, algal oil and many plant seeds oils. Omega-3 fatty acids provides many benefits to human health with regard to its cardiovascular diseases prevention, anti-inflammation and possibly anti-cancer functions.
The ω−6 fatty acids are PUSFs with a double bond starting after the sixth carbon atom from the methyl end of the carbon chain. The most common ω−6 fatty acids include linoleic acid (LA, C18:2) and arachidonic acid (AA, C20:4). Linoleic acid is an essential fatty acid to human body although it is abundantly available from plant originated food oils (palm, soybean, rapeseed, and sunflower). Arachidonic acid is not an essential fatty acid to human body since it can be synthesized from linoleic acid. Meat, dairy products, eggs are the major food source for arachidonic acid. Due excess intake of ω−6 fatty acids in modern human life style, the negative impact of this type of fatty acids to human health is more noted than their important structural and regulatory functions in a normal cell. Excess intake of ω−6 fatty acids is often associated with heart attacks, thrombotic stroke, arrhythmia, arthritis, osteoporosis, inflammation, mood disorders, obesity, and cancer. For people carrying the APOA5 SNP -1131T>G, an intake of ω−6 fatty acids exceeds 6% of the total energy becomes harmful (See the APOA5 and Triglycerides Management review).
Table 1. Common natural fatty acids in human diet
| Types |
Common name |
Structure |
Source |
| SFA |
Lauric |
C12 : 0 |
Coconut fat, palm kernel oil |
| Myristic acid |
C14 : 0 |
Mike, coconut fat |
| Palmitic 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, most dietary fat |
| ω-6 PUFA |
Linoleic acid (LA) |
C18 : 2 |
Corn oil, soybean oil, sunflower seeds oil and peanut oil |
| Arachidonic acid (AA) |
C20 : 4 |
Small amount in animal fat |
| ω-3 PUFA |
α-Linolenic acid (ALA) |
C18 : 3 |
Flaxseeds 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 are the ones human body cannot synthesize, thus have to come from dietary intake. There are two essential fatty acids for human. On is the omega-3 fatty acid α-linolenic acid (ALA, C18:3) and the other the omega-6 fatty acid linoleic acid (LA, C18:2). Deficiency of essential fatty acids would lead to retarded growth, dermatitis, kidney lesion and early death.
Trans vs. cis fat
In unsaturated fatty acids, the orientation of the two hydrogen atoms adjacent to a double bond has a great impact on the chemical property of the molecule. When those two hydrogen atoms are orientated in opposite directions, they are called trans. When they are oriented in the same direction, they are cis. Most natural unsaturated fatty acids are cis. Trans fat is rare in natural food sources but is abundant in food industry as the result of artificial hydrogenation of natural oil. Trans fat is easier to process in food industry but the hydrogenation destroys the essential fatty acids and renders PUFAs the property of saturated fatty acids. Therefore, they are considered health hazard and are banned in some cities in the United States. The most abundant trans fat is found in the artificial butter margarine.
Fat as energy reservoir
In human and animals, excess calorie from diet, regardless if it is from carbohydrate or from fat, is converted to and stored as fat. But when the body requires this energy again, i. e. during fasting or starvation, the stored triglycerides are cleaved to give 3 fatty acid chains and 1 glycerol molecule in a process called lipolysis. The 3 fatty acids provide energy through a process called beta oxidation pathway. The resulting molecules of 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) and produces even more energy. The glycerol is converted to glucose, and gives cells energy via glycolysis pathway and TCA cycle. Fatty acids can also been converted into ketone bodies, which refer to three molecules acetone, acetoacetic acid, and beta-hydroxybutyric acid that are produced during fatty acids breaking down for energy in the liver and kidney. They are valuable energy source since they are water-soluble and easy to be 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. At conditions when the routine energy source glucose is limited (e.g., during fasting, strenuous exercise, low carbohydrate diet), the brain can get up to 70% energy from ketone bodies.
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Dietary fat digestion and absorption by human body
Dietary triglycerides cannot be absorbed by human cells directly. They have to go through a series of breaking down process by a family of enzymes called lipases. In the mouth, lingual lipase produced in the salivary gland partially break down the triglycerides to fatty acids and diacylglycerols. This digestion continues in the stomach by the gastric lipase and in the small intestine by the pancreatic lipase, resulting in a mixture of free fatty acids and monoacylglycerols. The free fatty acids and monoacylglycerols are then absorbed by the intestinal enterocytes. In the enterocytes, the free fatty acids and monoacylglycerols, along with cholesterol and the lipoprotein Apo B48 are assembled into nascent chylomicrons, which are then released to blood circulation for transporting to other tissues.
Fat transportation
Triglycerides from diet or synthesized in the liver, are transported in the form of lipoproteins. The dietary triglycerides are mainly transported in the form of chylomicrons and liver triglycerides mainly in VLDL. Different lipoprotein and their metabolism are described in another review (cholesterol and lipoprotein 101). 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, by albumin. In hepatocytes, NEFAs can be used for energy production, re-packaged into triglycerides and exported as very low density lipoproteins (VLDL) or stored within the liver, or converted to ketone bodies.
Triglycerides biosynthesis
Triglycerides are synthesized in many tissues including the gut, the liver, the adipose tissue, mammary gland, and muscle. The starting substrates for triglycerides biosynthesis are fatty acids and glycerol-3-phosphate, an intermediate of glycolysis pathway. The free fatty acids are first activated to 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 unsaturated ones. The enzyme phosphatidate phosphohydrolase then removes the phosphate group at the third position to produce diglyceride. This is the rate-limiting step of triglyceride biosynthesis. Finally the free hydroxyl group at the diglyceride is esterified with the third fatty acyl-CoA molecule, either saturated or unsaturated, to form a glyceride molecule. In the gut, the major source of fatty acids is from diet. In the liver, the fatty acids may be supplied by the circulating NEFAs or by de novo fatty acids biosynthesis.
Fatty acids biosynthesis
In humans, de novo fatty acids biosynthesis, also refers to de novo lipogenesis, occurs predominantly in the liver and lactating mammary glands, and, to a lesser extent, the adipose tissue. De novo fatty acids biosynthesis serves the function of converting excess dietary carbohydrate into triglycerides.
In fatty acid biosynthesis, acetyl-CoA is the direct precursor and malonyl-CoA is the actual substrate. All the other carbons come from the acetyl group of acetyl-CoA but only after it is modified to malonyl-CoA by the addition of CO2 using the biotin cofactor of the enzyme acetyl-CoA carboxylase. Formation of malonyl-CoA is the commitment step for fatty acid synthesis, because malonyl-CoA has no metabolic role other than serving as a precursor to fatty acids. The large multi-enzyme complex fatty acid synthase (FAS) carries out the chain elongation steps through the sequential addition of two carbon units at a time, with the carbons donated by malonyl-CoA. The final product of the series of reactions catalyzed by FAS is palmitate (C16:0). Palmitate can be incorporated into triglycerides or further elongated by enzymes such as elongation of long-chain fatty acids family member 6 (ELOVL6), which catalyzes the addition of two-carbon units primarily to 12, 14, and 16-carbon fatty acid chains. 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 changing dietary exposures.
Fat as energy supply
When fatty acids are required by tissues for energy or other purposes, they are released from the triacylglycerides mainly by the actions of three enzymes, hormone-sensitive lipase, adipose triacylglycerol lipase and monoacylglycerol lipase. Free fatty acids released by the combined action of these enzymes are exported into the plasma as NEFAs for transport to other tissues. The glycerol released is transported to the liver for metabolism by either glycolysis or gluconeogenesis.
The hormone-sensitive lipase is regulated by the hormones insulin, glucagon, norepinephrine, and epinephrine. Glucagon is associated with low blood glucose, and epinephrine is associated with increased metabolic demands. In both situations, energy is needed, and 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.
The adipose triacylglycerol lipase was discovered relatively recently. It is specific for triacylglycerols yielding diacylglycerols and free fatty acids as the main products. It is now believed to be rate limiting for the first step in triacylglycerol hydrolysis. Regulation of the enzymatic activity is assumed to involve hormonal factors, but these have yet to be characterized.
The monoacylglycerol lipase is believed to be the rate-limiting enzyme in monoacylglycerol hydrolysis, i.e. the final step in triacylglycerol catabolism releasing free glycerol and fatty acids, and is found in the cytoplasm, the plasma membrane, and in lipid droplets. It is specific for monoacylglycerols and has no activity against di- or triacylglycerols.
Major references
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. Euro J Hum Genet 17, 620–628
Simopoulos AP (1999). Essential fatty acids in health and chronic disease. Am J Clin Nutr. 70(3 Suppl):560S-569S. PMID: 10479232
Strable and Ntambi, 2010. Genetic control of de novo lipogenesis: role in diet-induced obesity. Crit Rev Biochem Mol Biol. 45(3): 199–214.
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