Fatty Acid Synthesis: How fat is made

Fat is made and stored in the body any time that excess calories are taken in. It does not matter if these calories come from fat, carbohydrate, or protein. Actually, the major source of the carbon used to make fat is from carbohydrate. In general, both glucose and amino acids can be changed to Acetyl CoA, which is made into fatty acids, which is made into triglycerides, which is packaged into VLDL and circulates in the blood. Fatty acids may also be made into glycerophospholipids, which have a glycerol backbone, 2 fatty acids, and a head group.
Fatty acids are made in the liver. This is stimulated by the hormone insulin that is released after a meal. The creation of fatty acids is basically the reverse of oxidation, or the breakdown of fatty acids for energy in that, instead of breaking off two carbon units at a time, it adds them on until the long chain fatty acid palmitate is formed. However, fatty acid synthesis occurs through a different pathway with different enzymes involved. Also, fatty acids are synthesized in the cytoplasm - while oxidation occurs in the mitochondria.
In order for fatty acids to be made, acetyl CoA is needed in the cytoplasm. However, acetyl CoA cannot cross the mitochondrial membrane to get there. Acetyl CoA exists in the mitochondria because it is synthesized from pyruvate from glycolysis, using the enzyme pyruvate dehydrogenase. Normally it would enter the Krebs cycle to make energy, but when excessive carbohydrate is taken in, there is excess CoA. At that point, a special reaction takes place so that the CoA can enter the cytoplasm and make fatty acids.
With a carboxylation reaction requiring the enzyme pyruvate carboxylase and the water soluble vitamin biotin, oxaloacetate (OAA) is formed from pyruvate. This combines with acetyl CoA through a condensation reaction, forming citrate. Citrate can cross through to the cytosol, and once there it breaks back into Acetyl CoA and OAA. The acetyl CoA can now be used for fatty acid synthesis, and the OAA is changed back to pyruvate and starts the conversion process over again. This happens by first changing OAA to malate through a dehydrogenase reaction, which requires NADH. Then, malic enzyme removes one carbon and releases CO2 and NADPH, changing the malate (a 4 carbon molecule) to pyruvate (a 3 carbon molecule). The NADPH produced is then used in fatty acid synthesis. This is important, because fatty acid synthesis requires a lot of NADPH. This reaction, along with the pentose phosphate pathway, are the major sources of NADPH for fatty acid synthesis.
Acetyl CoA is converted to malonyl CoA by adding CO2 in a carboxylation reaction that requires both biotin and ATP. Malonyl CoA is the intermediate used in the fatty acid synthase complex, so at this point we are ready to make some fatty acids!
Fatty acid synthase is a large enzyme system that consists of a pantothenyl sulfhydral (P-SH) group and a cysteinal sulfhydral (C-SH) group. Acetyl CoA attaches to the P-SH group, then to the C-SH group. Malonyl CoA attaches to the P-SH group. Condensation occurs, releasing CO2 from the malonyl part. Next, a series of 4 more reactions occur which results in the addition of 2 carbons.
1. Two hydrogen are added from NADPH at the 2nd carbonyl carbon
2. Water is removed, making a double bond
3. NADPH gives more hydrogen to make the bond saturated.
4. SH is flipped to make the pantothenyl group open.
At this point, a 2 carbon unit has been added, and malonyl CoA can attach again and start the cycle over until palmitate has been made.
At this point, triglycerides may be made, or the fatty acids may be elongated or desaturated. Highly unsaturated fatty acids and a class called eicosanoids are needed for important processes in the body, including usage by the brain. However, the human body cannot desaturate an 18:1 fatty acid to 18:2 (linoleic acid) or 18:3 (linolenic acid). That's why we call these two fatty acids essential - we must obtain them from the diet.
Triglycerides are synthesized from fatty acids in the liver and adipose tissue. The process requires glycerol 3-phosphate, which is made in different ways in both tissues. The liver contains the enzyme glycerol kinase, which can change glycerol to glycerol 3-P by using ATP. The liver can also reduce the dihydroxyacetone phosphate (DHAP) from glycolysis using NADH. The adipose tissue can only do the latter, because it does not contain glycerol kinase. Either way, 2 fatty acyl CoA's are added to the glycerol 3-P to form phosphatidic acid. The phosphate group comes off, making it into a diacylglycerol. Last, another fatty acid group comes in to form a triglyceride.
The triglycerides in the liver are packaged together with cholesterol, cholesterol esters, phospholipids, and proteins (mainly ApoB-100) to form a VLDL. VLDL is composed mostly of triglyceride. Upon entering the blood the VLDL is a nascent, or new/young VLDL. As it circulates, it acquires Apo C2 and Apo E proteins from HDL, making it a mature VLDL particle. Apo C2 activates lipoprotein lipase (LPL) located at adipose and muscle cells. LPL digests the VLDL, causing triglycerides to come off. Since muscle cells need fatty acids for energy, its LPL activity is high even when the level of VLDL and chylomicrons in the blood are low. However, adipose tissue's major function is to store fatty acids. Therefore, it only uses its LPL when VLDL levels are very high, or following a meal. A meal rich in carbohydrates (namely simple sugars) results in a large amount of triglyceride being produced, leading to overproduction of VLDL. This condition is known as transient hypertriglyceridemia. As TG is broken down by the LPL in the adipose tissue, fatty acids go to storage and glycerol returns to the liver. This is how excess sugar in the diet is stored as fat and results in weight gain.
Eventually the VLDL becomes and IDL, then LDL as more of it its triglyceride content is digested.
In the fasted state, level of insulin goes down and the level of glucagon goes up. This stimulates the release of triglycerides from adipose lipase. The triglycerides are digested to fatty acids and glycerol and go to the liver. Fatty acids go through oxidation for energy, or are used to make ketones. Glycerol can be used in gluconeogenesis, or the making of glucose from non carbohydrate sources, and used for energy.