Synthesis of Triglycerides Fatty acids are stored for future use as triacylglycerols (TAGs) in all cells, but primarily

in adipocytes of adipose tissue. TAGs constitute molecules of glycerol to which three fatty acids have been esterified. The fatty acids present in TAGs are predominantly saturated. The major building block for the synthesis of TAGs, in tissues other than adipose tissue, is glycerol. Adipocytes lack glycerol kinase, therefore, dihydroxyacetone phosphate (DHAP), produced during glycolysis, is the precursor for TAG synthesis in adipose tissue. This means that adipoctes must have glucose to oxidize in order to store fatty acids in the form of TAGs. DHAP can also serve as a backbone precursor for TAG synthesis in tissues other than adipose, but does so to a much lesser extent than glycerol.

Phosphatidic acid Synthesis

Triglyceride Synthesis

The glycerol backbone of TAGs is activated by phosphorylation at the C-3 position by glycerol kinase. The utilization of DHAP for the backbone is carried out through either of two pathways depending upon whether the synthesis of triglycerides is carried out in the mitochondria and ER or the ER and the

peroxisomes. In the former case the action of glycerol-3-phosphate dehydrogenase, a reaction that requires NADH (the same reaction as that used in the glycerol-phosphate shuttle), converts DHAP to glycerol-3-phosphate. Glycerol-3-phosphate acyltransferase then esterifies a fatty acid to glycerol-3phosphate generating the monoacylglycerol phosphate structure called lysophosphatidic acid. The second reaction pathway utilizes the peroxisomal enzyme DHAP acyltransferase to fatty acylate DHAP to acyl-DHAP which is then reduced by the NADPH-requiring enzyme acyl-DHAP reductase. An interesting feature of the latter pathway is that DHAP acyltransferase is one of only a few enzymes that are targeted to the peroxisomes through the recognition of a peroxisome targeting sequence 2 (PTS2) motif in the enzyme. Most peroxisomal enzymes contain a PTS1 motif. For more information on peroxisome enzymes see the Zellweger syndrome page. The fatty acids incorporated into TAGs are activated to acyl-CoAs through the action of acyl-CoA synthetases. Two molecules of acyl-CoA are esterified to glycerol-3-phosphate to yield 1,2-diacylglycerol phosphate (commonly identified as phosphatidic acid). The phosphate is then removed, by phosphatidic acid phosphatase (PAP1), to yield 1,2-diacylglycerol, the substrate for addition of the third fatty acid. Intestinal monoacylglycerols, derived from the hydrolysis of dietary fats, can also serve as substrates for the synthesis of 1,2-diacylglycerols. Recent studies have identified a critical role for the enzyme PAP1 in overall TAG and phospholipid homeostasis. In the yeast Saccharomyces cerevisiae, the PAP1 gene was identified as Smp2p and the encoded protein was shown to be the yeast ortholog of the mammalian protein called lipin-1. The fission yeast lipin-1 ortholog is identified as Ned1p. Lipin-1 is only one of four lipin proteins identified in mammals. The lipin-1 gene (symbol = LPN1) was originally identified in a mutant mouse called the fatty liver dystrophy (fld) mouse. The mutation causing this disorder was found to reside in the LPN1 gene. There are three lipin genes with the LPN1 gene encoding two isoforms derived through alternative splicing. These two lipin-1 isoforms are identified as lipin-1A and lipin-1B. Mutations in the LPN2 gene have recently been associated with Majeed syndrome which is characterized by chronic recurrent osteomyelitis, cutaneous inflammation, recurrent fever, and congenital dyserythropoietic anemia. In addition to the obvious role of lipin-1 in TAG synthesis, evidence indicates that the protein is also required for the development of mature adipocytes, coordination of peripheral tissue glucose and fatty acid storage and utilization, and serves as a transcriptional co-activator. The latter function has significance to diabetes as it has been shown that some of the effects of the thiazolidinedione (TZD) class of drugs used to treat the hyperglycemia associated with type 2 diabetes are exerted via the effects of lipin-1. Lipin-1 has been shown to interact with peroxisome proliferator-activated receptor[PPAR ] co-activator 1 (PGC-1 ) and PPAR . The interactions of lipin-1 with these other transcription factors leads to increased expression of fatty acid oxidizing genes such as carnitinepalmitoyl transferase1, acyl CoA oxidase, and medium-chain acylCoA dehydrogenase (MCAD). The National Cholesterol Education Program guidelines for triglycerides are: Normal Borderline-high High Very high Less than 150 mg/dL 150 to 199 mg/dL 200 to 499 mg/dL 500 mg/dL or higher

What's the difference between triglycerides and cholesterol? Triglycerides and cholesterol are separate types of lipids that circulate in your blood. Triglycerides store unused calories and provide your body with energy, and cholesterol is used to build cells and certain hormones. Because triglycerides and cholesterol can't dissolve in blood, they circulate throughout your body with the help of proteins that transport the lipids (lipoproteins). In the Fredrickson classification of hyperlipide-mias, the general term for elevated lipids in the blood, hypertriglyceridemia is classified as four different types:
y

y y y

Type I: This is a rare disorder characterized by severe elevations in chylomicrons and extremely elevated triglyceride levels, always well above 1000 mg/dL and reaching as high as 10,000 mg/dL or higher. Because chylomicrons also contain cholesterol, blood cholesterol levels are also quite high. Type IIb: This is a mixed hyperlipidemia (high cholesterol and triglycerides) caused by elevations in both LDL and VLDL. Type III: This form is characterized by elevated total cholesterol and triglyceride levels. This type is easily confused with type IIb, but type III also features elevations in IDL. Type IV: This type is characterized by abnormal elevations of VLDL, with triglyceride levels almost always lower than 1000 mg/dL. Blood cholesterol levels are normal.

Table 1. Fredrickson Classification of Hyperlipoproteinemia Type I IIa IIb III IV V Serum elevation Lipoprotein elevation

Cholesterol and triglycerides Chylomicrons Cholesterol LDL*

Cholesterol and triglycerides LDL, VLDL** Cholesterol and triglycerides IDL*** Triglycerides VLDL

Cholesterol and triglycerides VLDL, chylomicrons

*LDL (low-density lipoprotein) **VLDL (very low-density lipoprotein) ***IDL (intermediate-density lipoprotein) y Type I is a rare disorder characterized by severe elevations in chylomicrons and extremely elevated triglycerides, always reaching well above 1000 mg/dL and not infrequently rising as high as 10,000 mg/dL or more. It is caused by mutations of either the lipoprotein lipase gene (LPL), which is critical for the metabolism of chylomicrons and very low-density lipoprotein (VLDL), or of the gene's cofactor, apolipoprotein (apo) C-II.Counterintuitively, despite

exceedingly high elevations of triglyceride and, in some cases, of total cholesterol, these mutations do not appear to confer an increased risk of atherosclerotic disease. This fact may have contributed to the unfounded belief that hypertriglyceridemia is not a risk factor for atherosclerotic disease. Although chylomicrons contain far less cholesterol than other triglyceride-rich lipoproteins do, when serum triglyceride levels are severely elevated, cholesterol levels can also be quite high.

Type IIb is the classic mixed hyperlipidemia (high cholesterol and triglyceride levels), caused by elevations in LDL and VLDL. Type III is known as dysbetalipoproteinemia, remnant removal disease, or broad-beta disease. Typically, patients with this condition have elevated total cholesterol and triglyceride levels and are easily confused with patients with type IIb hyperlipidemia. Patients with type III hyperlipidemia have elevations in intermediate-density lipoprotein (IDL), a VLDL remnant, and a significant risk for developing coronary artery disease. Type IV is characterized by abnormal elevations of VLDL, and triglyceride levels are almost always less than 1000 mg/dL. Serum cholesterol levels are normal. Type V is characterized by elevations of chylomicrons and VLDL. Triglyceride levels are invariably greater than 1000 mg/dL, and total cholesterol levels are always elevated. The LDL cholesterol level is usually low. Given the rarity of type I disease, when triglyceride levels above 1000 mg/dL are noted, the most likely cause is type V hyperlipidemia. Triglyceride levels greater than 1000 mg/dL increase the risk of acute pancreatitis, and because triglycerides are so labile, levels of 500 mg/dL or greater must be the primary focus of therapy. If a patient also has a high risk for a cardiovascular event, LDL-lowering therapy should be considered.