Adipose Tissue Dissolution and Hypertriglyceridaemia

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Lipid metabolism in cancer has been extensively studied, the main features being an important reduction in body fat content (particularly white adipose tissue) and a significant hyperlipaemia. Dissolution of the fat mass is the result of three different altered processes. First, there is an increase in lipolytic activity [1], which results in the release of large amounts of glycerol and fatty acids. Glycerol is basically directed to the liver, where it provides a gluconeogenic substrate, while fatty acids are used by other tissues as an alternative substrate to glucose. Interestingly, the oxidation of fatty acids is not suppressed by glucose [2], as opposed to what is observed during starvation, in which the rate of fatty acid oxidation is normalised by glucose administration. Although fatty acids seem to be a very poor substrate for very undifferentiated, malignant tumour cells, some studies have demonstrated that polyunsaturated fatty acids (linoleic and arachidonic acids) are able to promote tumour growth by stimulating mitosis [3]. These compounds seem to inactivate the GTPase-activating protein of the ras-mediated signal transduction pathways, thus stimulating cell division [3]. Second, an important decrease in the activity of lipoprotein lipase (LPL), the enzyme responsible for the cleavage of both endogenous and exogenous triacylglycerols (present in lipoproteins) into glycerol and fatty acids, occurs in white adipose tissue [1,4,5]; consequently, lipid uptake is severely hampered. Finally, de novo lipo-genesis in adipose tissue is also reduced in tumour-bearing states [1], resulting in decreased esterification and, consequently, decreased lipid deposition.

Hyperlipaemia in cancer-bearing states seems to be the result of an elevation in triacylglycerols and cholesterol. Hypertriglyceridaemia is the consequence of decreased LPL activity, which results in a decrease in the plasma clearance of both endogenous (transported as very-low-density lipoproteins, VLDL) and exogenous (transported as chylomicra) triacylglycerols. Muscaritoli et al. [6] clearly demonstrated that the fractional removal rate and the maximum clearing capacity (calculated at high infusion rates, when LPL activity is saturated) are significantly decreased after the administration of an exogenous triacylglycerol load to cancer patients. In tumour-bearing animals with a high degree of cachexia, there is also an important association between decreased LPL activity and hypertriglyceridaemia [7, 8] (Fig. 1). Another factor that could contribute to the elevation in circulating triacylglycerols is an increase in liver lipogenesis [9].

Hypercholesterolaemia is often seen in tumour-bearing animals and in humans with cancer [10-12]. Interestingly, most cancer cells show an altered regulation in cholesterol biosynthesis, with a lack of feedback control on HMG-CoA reductase (3-hydroxy-3-methyl glutaryl CoA reductase), the key enzyme in the regulation of cholesterol biosynthesis. Cholesterol perturbations during cancer include changes in lipoprotein profiles, in particular an important decrease in the amount of cholesterol transported in the high-density lipoprotein (HDL) fraction. This has been observed in both experimental animals and human subjects [10-12]. HDL plays an important role in the transport of excess cholesterol from extrahepatic tissues to the liver for reutilisation or excretion into bile (reverse cholesterol transport). It is thus conceivable that the observed low levels of HDL-cholesterol are related, at least in part, to a decreased cholesterol efflux to HDL, as a consequence of increased utilisation and/or storage in proliferating tissues, such as neoplasms. However, since precursor particles of HDL are thought to derive from lipolysis of triacylglycerol-rich lipoproteins, such as VLDL and chylomicra [13], and since a significant positive correlation between plasma HDL-cholesterol and LPL activity in adipose tissue has been reported [13], the possibility that the low HDL-cholesterol concentrations observed during tumour growth are secondary to the decreased triacylglycerol clearance from plasma, as a result of LPL inhibition, must also be considered.

The elevation of circulating lipid therefore seems to be a hallmark of cancer-bearing states, to the extent that some authors have suggested that plasma levels can be used to screen patients for cancer [14].

Fig. 1. Main metabolic pathways linked to fat accumulation/dissolution in adipose tissue. As a result of tumour burden, fat loss is accelerated due to: (1) decreased glucose uptake, (2) decreased fatty acid synthesis, (3) decreased triacylglycerol uptake through LPL, (4) decreased esterification, and (5) increased lipolysis. Enhanced hepatic production of VLDL, together with its reduced clearance contributes to the hypertriglyceridaemia of the cachectic patient, one of the hallmarks of wasting

Fig. 1. Main metabolic pathways linked to fat accumulation/dissolution in adipose tissue. As a result of tumour burden, fat loss is accelerated due to: (1) decreased glucose uptake, (2) decreased fatty acid synthesis, (3) decreased triacylglycerol uptake through LPL, (4) decreased esterification, and (5) increased lipolysis. Enhanced hepatic production of VLDL, together with its reduced clearance contributes to the hypertriglyceridaemia of the cachectic patient, one of the hallmarks of wasting

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