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Introduction

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High-Yield Terms

  • Triglyceride: also called triacylglyceride or triacylglycerol, major storage form of lipid in the body, composed of a glycerol backbone and 3 esterified fatty acids

  • Phospholipid: major lipid component of all cell membranes, composed of a glycerol backbone esterified to 2 fatty acids with phosphate esterified to the sn3 position, the phosphate group, with an esterified alcohol, is referred to as the polar head group of phospholipids

  • Lipin: a family of enzymes exhibiting both phosphatidic acid phosphatase activity involved in triglyceride synthesis and transcriptional coactivator activity regulating expression of genes involved in lipid metabolism and adipocyte differentiation

  • Plasmalogens: are glycerol ether phospholipids mainly of 2 types: alkyl ether (–O–CH2–) and alkenyl ether (–O–CH=CH–); the plasmalogen platelet-activating factor (PAF) is one of the most potent biological lipids

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Synthesis of Triglycerides

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Triglycerides (TGs) constitute molecules of glycerol to which 3 fatty acids have been esterified. The fatty acids present in TGs are predominantly saturated. The major building block for the synthesis of TGs, in tissues other than adipose tissue, is glycerol. Adipocytes lack glycerol kinase; therefore, dihydroxyacetone phosphate (DHAP), produced during glycolysis, is the precursor for TG synthesis in adipose tissue. This means that adipocytes must have glucose to oxidize in order to store fatty acids in the form of TG. DHAP can also serve as a backbone precursor for TG synthesis in tissues other than adipose tissue, but does so to a much lesser extent than glycerol.

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The glycerol backbone of TG is activated by phosphorylation at the sn3 position by glycerol kinase. The utilization of DHAP for the backbone is carried out through either of 2 pathways depending on whether the synthesis of TG is carried out in the mitochondria and ER or the ER and the peroxisomes. In the first situation, the action of glycerol-3-phosphate dehydrogenase (the same reaction as that used in the glycerol-phosphate shuttle) reduces DHAP to glycerol 3-phosphate. Glycerol-3-phosphate acyltransferase (GPAT) then esterifies a fatty acid to glycerol 3-phosphate, generating the monoacylglycerol phosphate structure called lysophosphatidic acid. The expression of the GPAT gene is under the influence of the transcription factor ChREBP (see Chapter 19).

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The second reaction pathway utilizes the peroxisomal enzyme DHAP acyltransferase to fatty acylated 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.

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The fatty acids incorporated into TGs 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 ...

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