Lipid metabolism seems to be particularly involved with and affected by cytokines. Early studies [85, 86] pointed out the cachexia-promoting effects of TNF, IL-1,and IFNs.
Initially, the cachexia seen in different extreme clinical situations was thought to be due to TNF, which for that reason was also called cachectin. The injection of TNF into animals, while causing hypertriglyceridaemia and reduction of appetite and water intake, does not cause cachexia if the correct amount of calories is given . Many studies have shown, instead, that disturbances in lipid metabolism, anorexia, and weight loss, all of which lead to cachexia, are due to the combined action of TNF, IL-1, IL-6, and IFN-y [85, 86], whose production is stimulated by infection and neoplasms [78,82].
Hypertriglyceridaemia starts mainly through the inhibition of LPL, which regulates the clearance of plasma triglycerides (Fig. 8) and energy production from lipids (Table 4).
LPL is inhibited by TNF and estradiol, and is stimulated by progestins. An increase in liver lipo-genesis is associated with increased production of very-low-density lipoprotein (VLDL). In the fat cell, LPL inhibition causes a reduction of lipogene-sis with consequent lipolysis. These effects can be avoided by the administration of inhibitors of prostaglandin synthesis .
The increase in plasma triglycerides observed in cachexia is due not only to LPL inhibition and clearance, but also to increased VLDL synthesis from free fatty acids (FFA), resulting from the lipolysis of peripheral fat . By blocking lipoly-sis in the fat cell, for example with phenyl-isopropyl-adenosine, FFA and plasma triglycerides can be reduced [83, 89]. This indicates that liver synthesis of VLDL starts from FFA mobilised from peripheral fat, re-esterified to triglycerides by the liver, and secreted as VLDL  - a typical exam-
Fig. 8. Role of lipoprotein lipase (LPL) in lipid metabolism. FFA, Free fatty acids; TG, triglyceride; VLDL, very-low-density lipoprotein
Table 4 . Role of LPL in tissues
Muscle (cardiac, skeletal) White adipose tissue Brown adipose tissue Lactating breast Lung Brain
Adrenal, kidney, spleen, foetal liver
Milk triglyceride synthesis
Unknown aPutative ple of the energy-wasting 'futile' metabolic cycle (Fig. 9). Fatty acids mobilised from peripheral fat reach the liver, where they escape oxidation, are then re-esterified to triglycerides, and pass into blood circulation as VLDL. These lipoproteins return in the adipose tissue to be hydrolysed again to fatty acids by LPL and are stored in fat cells as triglycerides . This vicious cycle, caused by
TNF, IL-1, IL-6, and IFN-y, does not produce energy (ATP), but rather consumes it, thereby contributing to weight loss.
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