Lipid Metabolism in Cachexia

Enzo Manzato, Giovanna Romanato

In this chapter we will review the alterations of lipoprotein metabolism observed in cachexia. Other aspects of lipid metabolism in cachexia, in particular those regarding adipose tissue, are covered in other chapters. Lipoproteins are macro-molecules circulating in blood and they are quite easily measured in the clinical chemistry laboratory. For this reason lipoproteins can be used to monitor the alterations of lipid metabolism in several clinical conditions, including cachexia.

All lipids, except free (non-esterified) fatty acids (FFA), are transported in blood in the form of lipoproteins in association with specific proteins (apolipoproteins). The major lipids found in human plasma lipoproteins are triglycerides, phospholipids and cholesterol (free and esteri-fied) [1].

FFA are transported from their storage site (i.e. adipose tissue) to the sites of utilisation (liver and muscles). The release of FFA from adipose tissue is regulated by a hormone-sensitive lipase (which is activated by noradrenaline and gluco-corticoid hormones) and is promoted by prolonged fasting, acute stress, and lack of insulin. The adipose tissue hormone-sensitive lipase is thus involved in removing FFA from the triglycerides present within the adipocytes.

Triglycerides are esters of glycerol with fatty acids and they are produced in the small intestine during fat absorption or in the liver and in the adipose tissue. Triglycerides have a relatively short half-life in the plasma and they are hydrol-ysed by lipolytic enzymes (lipoprotein lipase) in various organs (adipose tissue, muscles, liver). The lipoprotein lipases are involved in extraction of fatty acids from plasma triglycerides and these FFA are used for storage in adipose tissue, for energy production in several organs, or for lipid synthesis in the liver.

Several phospholipids are found in plasma but the two most abundant are phosphatidylcholine (also called lecithin) and sphingomyelin. Most of the plasma phosholipids are synthesised in the liver. Phospholipids are essential components of all cellular membranes and they have a key role in maintaining non-polar lipids (like triglycerides and cholesterol esters) in a soluble state within lipoproteins.

Cholesterol is a sterol containing a hydroxyl group that can be non-esterified (free cholesterol) or esterified with one of several long-chain fatty acids (mostly linoleic and oleic acid). Free cholesterol is an essential component of all cell membranes, while two thirds of the cholesterol present in plasma is esterified. Plasma cholesterol is produced by the liver and in part it is derived from intestinal absorption. The major metabolites of cholesterol are the bile acids, which are synthe-sised exclusively by the liver.

To form lipoproteins, lipids are associated with apolipoproteins. The role of apolipoproteins is both structural and functional. In fact, apolipopro-teins have amphipatic properties, i.e. they can solubilise apolar lipids (triglycerides and cholesterol esters) in an aqueous environment. The most important apolipoproteins found in human plasma are apo AI, AII, B100, B48, CI, CII, CIII and E. Some apolipoproteins are cofactors of important enzymes involved in lipoprotein metabolism (e.g. apo CII for lipoprotein lipase, apo AI for lecithin-cholesterol acyl transferase) or are involved in the receptor-mediated lipoprotein uptake (e.g. apo B100 and apo E for the low-density lipoprotein [LDL] receptor).

Four major classes of lipoproteins can be isolated from plasma: chylomicrons, very-low-density lipoproteins (VLDL), LDL and high-density lipoproteins (HDL). Chylomicrons are produced by the small intestine during fat absorption: they consist mainly of triglycerides that are catabolised by lipoprotein lipase. VLDL are triglyceride-rich lipoproteins produced by the liver, which are transformed into LDL by lipoprotein lipase. LDL are cholesterol-rich lipoproteins that can be used by peripheral tissues for cholesterol supply or by the liver for cholesterol catabolism through biliary acids. LDL are the major cholesterol-carrying lipoproteins of human plasma, containing about two thirds of plasma cholesterol. HDL contain mainly phospholipids and small amounts of cholesterol that is acquired from peripheral tissue to be released to the liver ('inverse' cholesterol transport).

Plasma lipid and lipoprotein concentrations are regulated by genetic, metabolic and dietary factors. Several genetic (primary) forms of both hyperlipidaemia and hypolipidaemia have been described, as well as secondary (or acquired) forms due to systemic disease such as diabetes, endocrine diseases (thyroid, hypophysis) or organ failure (liver, kidney)(Table 1) [2]. Secondary hyperlipidaemias are also produced by some drugs. In association with genetic background, dietary habits have an important role in modulating plasma lipid concentrations: therefore, the alterations of lipid metabolism in cachexia must be considered taking into account all these factors.

Since cachexia is a common feature of several

Table 1. Secondary causes of lipoprotein abnormalities that may be present in patients with cachexia

1. Reduced LDL cholesterol: chronic infections (AIDS, tuberculosis), chronic liver diseases, hyperthyroidism, malabsorption (short bowel, blind-loop syndrome, coeliac disease, pancreatic exocrine insufficiency, giardiasis), malnutrition, monoclonal gammopathy, myeloproliferative diseases

2. Increased LDL cholesterol: anorexia nervosa, drugs (cyclosporine, progestogens, thiazides), obstructive liver disease

3. Increased VLDL (hypertriglyceridaemia): alcohol, chronic renal failure, drugs (beta blockers, oestrogen, glucocorticoids, isotretinoin, protease inhibitors, thiazides), monoclonal gammopathy (lymphoma, multiple myeloma), ileal bypass surgery, lipodystrophy, poorly controlled diabetes mellitus, sepsis, stress, systemic lupus erythematosus

4. Reduced HDL cholesterol: anabolic steroids, beta blockers, cigarette smoking, malnutrition different illnesses (including cancer, sepsis, chronic heart failure, thyroid diseases, severe liver diseases, rheumatoid arthritis and AIDS), the alterations of lipid metabolism observed in these patients may have different causes, related to specific organ involvement, dietary modifications, fat absorption or drugs.

The main lipid abnormalities found in cachexia are related to reduced food intake, enhanced lipid mobilisation from the adipose tissue, reduced lipo-genesis in the liver, and reduced lipoprotein lipase activities (Table 2). The mechanisms responsible for the lipid alterations are malabsorption, dietary deficiency and metabolic dysfunctions. Anorexia can be related to the primary disease or to side-effects of drugs. These abnormalities are usually associated with low HDL cholesterol and variable triglyceride concentrations [3].

In patients with a variety of tumours, VLDL triglycerides accumulate in plasma as a result of decreased lipoprotein lipase activity. In fact, both the extrahepatic and hepatic lipoprotein lipase activities are decreased in cancer patients with varying degrees of weight loss, the levels of these activities being correlated with the per cent body weight lost [4]. On the other hand, fasting in healthy humans is associated with increased lipase activities and reduced triglyceride levels [5].

In patients with cachexia, the production of cytokines is frequently altered. Several cytokines inhibit the lipoprotein lipase activities, thus reducing plasma triglyceride catabolism and preventing fatty acid deposition in the adipose tissue [6].

Interleukin-6 (IL-6) reduces lipase activities and may play a role in inducing cancer cachexia, but in cancer patients IL-6 does not correlate with lipase activities and therefore IL-6 does not seem to be involved in the lipid alterations of these patients [7].

Table 2. Pathophysiological alterations involved in the lipid abnormalities of patients with cachexia

Impaired lipoprotein lipase activities Increased lipolysis from adipose tissue Reduced total body lipids Reduced fat synthesis

Interleukin-2 (IL-2),when used to treat refractory cancers, causes severe hypocholesterolaemia, associated with reduction of both lipoprotein lipase and lecithin:cholesteryl acyltransferase (LCAT) activities. The LCAT reduction has been associated with the presence of abnormal lipopro-teins in plasma [8].

Tumour necrosis factor (TNF)-a inhibits lipoprotein lipase by down-regulation of the protein expression of this lipase [9], thus reducing the tryglyceride catabolism in VLDL [10] and the fatty acid deposition in the adipocytes. These observations may explain why hypertriglyceri-daemia is sometimes present in patients with cachexia. On the other hand, TNF-a can increase the activity of the adipose tissue hormonesensitive lipase, thus leading to an increased lipol-ysis from the adipocytes [11].

Hypocholesterolaemia is commonly found in patients with acute leukaemia, lung cancer and solid tumours, due to the high LDL-receptor activity of cancer cells. In some of these patients, the LDL-receptor activity is inversely correlated with plasma-cholesterol concentration. It has been hypothesised that this hypocholesterolaemia might be due to three different mechanisms: (1) enhanced uptake of plasma LDL by cancer cells; (2) increased transport of cholesterol from cancer

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  • leon
    What is cachexia disease asociated with lipid ?
    7 months ago

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