Lipogenesis

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Lipogenesis describes the process by which triglycerides circulating in the blood are hydrolysed to form NEFAs, which can be taken up by adipocytes and re-esterified in the form of intracellular triglycerides. NEFA are transported bound to albumin. However, cholesterol, triglycerides and phospholipids are transported as one of six different forms of lipoprotein complexes (three of which are the very-low density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL). Lipoproteins consist of a hydrophobic core of triglyceride and cholesteryl esters surrounded by phospholipids and proteins, these being apoproteins (the major ones being apoprotein E, C and B; Ganong, 1997). The most important pathway regulating the process for accumulating triglycerides in human tissue is the lipoprotein lipase (LPL) pathway.

Adipose tissue triglyceride depots are the major storage form for energy in the body and account for 10-30 per cent of body weight. In humans, the liver is the main anatomical site for lipogenesis, with the adipocyte making only a limited contribution. Dietary and hepatic sources form the main source of lipid for adipocytes with their uptake being regulated by LPL. LPL is a 55-kDa protein which is an evolutionarily conserved enzyme that catalyses the rate-limiting step in the lipogenic pathway (Wion et al., 1987).

The enzyme is activated by apolipoprotein Cn that is present different forms of lipoprotein complexes previously mentioned (Eckel, 1989). Upon activation, LPL hydrolyses the core triglyceride of the lipoproteins, including VLDL and chylomicrons. The VLDL particles contain the highest concentrations of tri-acylglycerol during the fasting state, whereas the chylomicrons predominantly carry triacylglycerols that have been absorbed following a meal and contain neutral fat. The hydrolysis of the lipoprotein results in the production of HDL that essentially contain the remnant particles of the chylomicrons. Although the process of hydrolysis of triglyceride takes place on the capillary lumi-nal surface where LPL is attached to heparin sulphate proteoglycans, LPL is actually synthesized and secreted by adipocytes. In the cytoplasm of the cell, re-assembly into triglycerides occurs through the esterification of NEFA with glycerol-3-phosphate (Figure 4.2). Although glycerol-3-phosphate in adipocytes can be generated from glucose via glycolysis, there is little de novo lipoge-nesis in human adipose tissue with the lipid backbone of triglyceride almost exclusively coming from the imported NEFA rather than primarily synthesized from glucose. Although a previous study has highlighted that glycerol

60 PATHOGENESIS OF OBESITY-RELATED TYPE 2 DIABETES Endothelium

60 PATHOGENESIS OF OBESITY-RELATED TYPE 2 DIABETES Endothelium

Lipogenesis Lipolysis

LPL - lipoprotein lipase; TG - Triglyceride. Reproduced by permission of Blackwell Science

Figure 4.4 An overview of lipogenesis, lipolysis and some of the hormonal regulators.

LPL - lipoprotein lipase; TG - Triglyceride. Reproduced by permission of Blackwell Science

Figure 4.4 An overview of lipogenesis, lipolysis and some of the hormonal regulators.

itself cannot be used in triglyceride synthesis as adipocytes lack glyceroki-nase (Vaughan et al., 1965) which converts glycerol to glycerol-3-phosphate, recent data indicates that adipocytes also express glycerokinase when treated with rosiglitazone (Guan et al., 2002). Formation of triglycerides in adipose tissue involves several stages in which insulin has an important role although the regulation is not clearly understood (Figure 4.4). Insulin stimulates lipogenesis and acts partly by increasing the activities of lipogenic enzymes such as pyru-vate dehydrogenase, and acetyl CoA carboxylase as well as stimulating glucose uptake, through glucose transporter 4 (GLUT-4), therefore increasing the availability of pyruvate for fatty acid synthesis and glycerol-3-phosphate for their esterification.

Previous studies have shown that LPL levels are higher in obese individuals than lean subjects. In addition LPL levels are observed to be higher in women than men and higher in femoral adipose tissue than abdominal subcutaneous tissue. LPL has been shown to be under the hormonal regulation of catecholamines, insulin, growth hormone, sex steroids, glucocorticoids and cytokines (Kern et al., 1985; Fried et al., 1993; Kruszynska, 1997; Arner and Eckel, 1998) influencing lipogenesis activity.

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